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Conceptual Medicinal Chemistry

Adrenergic & Anti-Adrenergic Drugs

Chapter 1
Adrenergic & Anti-Adrenergic
Drugs

The branch of autonomic nervous system in which, norepinephrine (NE) is the neurotransmitter
between the nerve endings & the effector muscles is known as adrenergic nervous system.
Adrenergic drugs are chemical agents that exert their principle pharmacological & therapeutic
effects by either enhancing or reducing the activity of various components of sympathetic
divisions of ANS. In general, substances that exert effects similar to the stimulation of
sympathetic activity are known as sympathomimetics or adrenergic stimulants, while drugs
responsible for reduction in sympathetic activity are known as sympatholytics, anti-adrenergic
or adrenergic blocking agents.
Adrenergic Neurotransmitter
NE is the neurotransmitter of post-ganglionic sympathetic neurons. NE is synthesized & stored
in granules inside the nerve endings. It is liberated into the synapse during the depolarization in
quanta. Then, it migrates across synapses & binds to its
H OH
receptors on the target organs. Another endogenous
HO NHR
adrenergic receptor agonist is epinephrine (sym. adrenaline,
sympathin). This is synthesized & stored in adrenal
HO
medulla & released into circulation from adrenal medulla.
NE, R=H
Adrenaline is not released from peripheral sympathetic
Epi., R=CH3
nerve endings like NE. So, sometimes epinephrine is
referred to as neurotransmitter.
Both adrenaline & noradrenaline are chemically catecholamines (CAs). These compounds are
highly susceptible towards aerial & photo oxidation forming ortho-quinone compounds, which
on further reaction produce highly colored compounds. So, they are stored with antioxidants
such as ascorbic acid or sodium bisulphite in dark colored container. CAs are amphilic in nature
due to presence of acidic catecholic groups & basic amino group. At physiologic pH (7.4),

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
cationic form predominates (95%), followed by zwitter-ionic form (3%) & non-ionized form
(2%). This accounts for high water solubility of these compounds as well as other CAs such as
isoproterenol.

OH
OH OH
+
HO NH2R + - +
HO NH2R O NH2R

HO - or
O HO

cationic form (95%) zwitter-ionic form (3%)

Biosynthesis of catecholamines (Fig. 1.1)


Catecholamines are biosynthesized in adrenergic & dopaminergic neurons of CNS & ANS &
adrenal medulla. Essential amino acid L-tyrosine serves as precursor of CAs. It is synthesized
from related amino acid phenylalanine in the liver by enzyme p-hydroxylase. Tyrosine is taken
up from circulation by adrenergic neurons & chromaffin cells. In axoplasm, tyrosine is converted
into L-3,4-dihydroxyphenylalanine (L-Dopa) by tyrosine hydroxylase (tyrosine-3-mono-
oxygenase), an Fe2+ containing enzyme that utilizes tetrahydrobiopterin as cofactor & requires
molecular oxygen. This is rate-limiting step. Adrenergic nerve stimulation activates kinase that
phosphorylates tyrosine hydroxylase & increases activity. NE decreases the activity of tyrosine
hydroxylase. This feedback inhibition is due to competition between CA product & cofactor,
pterin. L-Dopa is decarboxylated to dopamine (DA) by a cytoplasmic & broad substrate specific
enzyme, L-aromatic amino acid decarboxylase that utilizes pyridoxal phosphate as cofactor &
also found in liver & kidney. This DA is reached into vesicles from neuron. In vesicles, DA is
stereospecifically hydroxylated at β-carbon atom (-OH group has R-configuration) to form
norepinephrine (NE) by Cu++ containing enzyme, dopamine-β-hydroxylase (dopamine-β-mono-
oxygenase) that utilizes ascorbic acid as cofactor. Depolarization initiates vesicle fusion with
plasma membrane & finally NE is extruded into synaptic cleft along with ATP & protein
“Chromogranin”.
In adrenal medulla, NE is converted into epinephrine by N-methylation. N-methylation is
achieved by cytoplasmic enzyme ‘phenylethanolamine-N-methyl transferase (PNMT)’.

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COOH PNMT is also

NH2
found in heart &
Phenylalanine brain in small
p-Hydroxylase (in liver) amount.

COOH
Epinephrine is
transported into
NH2
HO
L-Tyrosine storage granules of

Rate limiting step Tyrosine hyroxylase (Fe2+, O2, Biopterin as cofactor) chromaffin cells.
Storage of CAs:
HO
COOH In chromaffin cells,

HO NH2 NE is stored in the


L-3,4-Dihydroxyphenylalanine (L-Dopa)
form of a complex
L-Aromatic amino acid decarboxylase/ with ATP (in ratio
Cytoplasmic enzyme, pyridoxal phosphate as cofactor
L-Dopa decarboxylase
of 4:1). This
HO complex is
adsorbed in a
HO NH2

Dopamine
protein
chromogranin.
Dopamine-β-hydroxylase, Cu++, ascorbic acid as
ATP + Chromogranin A
cofactor Usually, each
OH

HO
vesicle in
peripheral
HO NH2

Norepinephrine (NE) adrenergic neuron


containing about
Transfer of 'CH3' group from S-adenosyl PNMT (adrenal medulla)
methionine 6000-15000
OH

HO
molecules of NE. In
adrenal medulla,
HO NHCH3
NA thus formed
Epinephrine

Fig 1.1 :Biosynthesis of catecholamines diffuses out in


cytoplasm, where it
is methylated by PNMT & converted into epinephrine. The cytoplasmic pool of CAs is kept
constantly by enzyme present in outer surface of mitochondria.

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Release of CAs
Depolarization of adrenergic neuron, triggers
Ca++
transient opening of voltage gated Ca++ channels
Ca++ Gates
leading to influx of Ca++. This influx triggers fusion
+
adenylcyclase
of storage vesicles with neuronal cell membrane, cAMP
ATP __

leading to out flux of NE & other content of Ca++


+ α2-adrenoceptor
NA

vesicles into synapse through exocytosis. Ex


ocy
tos
is

Granules also contain peptides like enkaphalins or NA

neuropeptide γ also release their material


Postsynaptic receptors
simultaneously. This release is modulated by
presynaptic inhibitory α2-receptors. (Fig 1.2)
Indirect acting sympathomimetics also induce release of NA, but they do by displacing NA from
the nerve ending binding sites & by exchange diffusion visiting amine carrier of uptake 1. This
process is not Ca++ dependent & not exocytotic.
Reuptake
The action of NE at adrenergic receptors is terminated by a combination of processes including
uptake into the neurons & extra neuronal tissues, diffusion away from synapse & metabolism.
Usually, primarily, action of NE is terminated by reuptake of CA at nerve terminals or recycling
through active transport uptake into presynaptic neuron. This process is termed as uptake 1. It
involves Na+/Cl- dependent transmembrane transporter having high affinity for NE. Upto 95% of
NE is removed from synapse by this process. This uptake can be blocked by cocaine & some
tricyclic antidepressants. Some amount of NE re-enters the sympathetic neuron & is transported
into storage granules by an H+-dependent transmembrane vesicular protein, where it is held in a
stable complex with ATP & chromogranin until sympathetic nerve activity or some other
stimulus causes it to be released into the synaptic cleft.
A less efficient uptake process, uptake 2 operates in a variety of other cells operates in a variety
of cells like glial, hepatic & myocardial cells. This process has low affinity for NE & operates in
higher concentration of NE. Actually it operates extraneuronal tissues.
NE taken into presynaptic neuron by uptake 1 is metabolized by a mitochondrial enzyme,
monoamine oxidase (MAO) & fraction of NE which escapes uptake 1 diffuses out of the synapse

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& is metabolized in extraneuronal sites by a cytosolic enzyme, catechol-O-methyl transferase
(COMT), that methylates the meta-hydroxyl groups.
Table1.1: Characteristics of Uptake1 & Uptake 2
S.No. Characteristic Uptake 1 Uptake 2

1. Transport of NE(in rat heart)


Vmax(nmol/gm/min) 1.2 100
2. Km 0.3 250
3. Specificity NE > Adr > Iso. Adr. > NE > Iso.
4. Location Neuronal Extraneuronal
5. Other substrates Methylnorepinephrine, NE, Dopamine, 5-HT,
Dopamine, 5-HT, Tyramine, histamine
antiadrenergics
6. Inhibitors Cocaine, TCAs, Normetanephrine,
phenoxybenzamine Phenoxybenzamine,
Steroid hormones

Metabolism (Fig. 1.3)


Monoamine oxidase (MAO), a mitochondrial enzyme (outer membrane) & catechol-O-methyl-
transferase (COMT), cytosolic enzymes are two principal enzymes involved in metabolism of
CAs. Both of these enzymes are distributed throughout body but higher concentration is found in
liver & kidney.
MAO leads to oxidative deamination of amino group attached to terminal C-atom of CAs,
producing aldehydes. There are two forms of MAO viz. MAO-A & MAO-B. Similarly, COMT
catalyses methylation of meta-hydroxyl group of a variety of catechol containing molecules.
COMT & MAO lack substrate specificity. They also further act on metabolites produced by
them.
NE is oxidatively deaminated by MAO to 3,4-dihydroxyphenylglycoldehyde (DOGPAL), which
is reduced to 3,4-dihydroxyphenylethyleneglycol by aldehydes reductase. This metabolite is
mainly released into circulation where it undergoes methylation by COMT in non-neuronal

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OH
HO NHR

HO
MA
O NE, R = H O
A
M OH
Epi., R = CH3
HO
OH CHO
HO COMT
HO
CHO
DOGPAL
HO
3,4-Dihydroxyphenylglycoldehyde
(DOGPAL) OH Aldehyde dehydrogenase

H 3 CO NHR
Aldehyde Reductase
OH
OH
HO
OH HO
HO
COOH
Normetanephrine, R = H
HO
HO metaepinephrine, R = CH3
3,4-dihydroxymendelic acid
3,4-Dihyroxyphenylethyleneglycol

MAO
COMT
COMT

OH OH
OH
OH
H 3CO H 3CO H CO
Alcohol 3
CHO Aldehyde COOH
dehydrogenase
HO HO dehyrogenase HO
3-Methoxy-4-hydroxyphenylethylene 3-Methoxy-4-hydroxyphenylethylene 3-Methoxy-4-hydroxyphenyl
glycol glycoldehyde mandellic acid
(Vanilliyl mandelic acid, VMA)

Fig. 1.3: Metabolism of NE & epinephrine by MAO & COMT

tissues to form 3-methoxy-4-hydroxyphenylethyleneglycol, which is further oxidized by alcohol


dehydrogenase followed by aldehydes dehydrogenase to 3-methoxy-4-hydroxymandelic acid
also known as vanillyl mandelic acid (VMA). VMA can be final product of several pathways of
NE metabolism. 3-Methoxy-4-hydroxyphenylethyleneglycol is its main precursor. At
extraneuronal sites such as liver, DOGPAL is mainly oxidized to 3,4-dihydroxymandelic acid by
aldehydes dehydrogenase. VMA is the final metabolite of NE & epinephrine, whereas dopamine
is excreted mainly as homovanillic acid (HVA). These products are usually conjugated with

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Adrenergic & Anti-Adrenergic Drugs
glucuronic acid before excretion in urine. Endogenous epinephrine is mainly excreted as
metaepinephrine & VMA.
Adrenergic Receptors & subtypes
Ahlquist was first to propose the existence of the two general types of adrenergic receptors in
mammals. He designated them as α & β receptors. Later postsynaptic α-receptors were referred
to as α1 (excitatory), while presynaptic as α2-adrenoceptors (inhibitory).
β-Adrenoceptors
Lands (1962) suggested β-receptors could also be subdivided into β1 & β2 subtypes. In 1984,
Arch et al. reported third β-subtype i.e. β3 in brown adipose tissue. The β1-receptors exhibit the
agonist potency in order isoproterenol > epinephrine = NE, while for β 2-receptors potency order
is isoproterenol = NE > epinephrine.
β1-receptors are mainly distributed in heart, where they mediate positive inotropic & chronotropic
effects of catecholamines. They are also found in JG cells of kidney, where these are involved in
increase in rennin secretion. β2-receptors are mainly located on smooth muscles of the body,
where they cause relaxation producing effects like bronchodilation & vasodilatation. In liver, β2-
receptors promote glycogenolysis. β3 receptors are located on brown adipose tissue & stimulate
lipolysis.
Table 1.3: Differences between β1, β2 & β3-adrenoceptors
S. Characteristics β1 β2 β3
No.
1. Location Heart, JG cells in Bronchi, blood Adipose tissue
kidney vessels, uterus,
g.i.t., urinary
tract, eye
2. Selective agonist Dobutamine Salbutamol, BRL 37344
terbutaline
3. Selective antagonist Metoprolol, ICI-118551, α- CGP20712A
atenolol methylpropranolol
4. Potency of NA as agonist Strong Weak Strong

α-Adrenoceptors

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α-Adrenoceptors are involved in control of CVS activities e.g., constriction of vascular smooth
muscle controlled by both postjunctional α1 & α2 receptors, though α1 action is predominant. In
heart, activation of α1 receptors results in selective inotropic response with little or no change in
HR.
Table 1.4: Differences between α1 & α2 receptors
S. No. Characteristics α1 α2
1 Location Post-junctional on effector Prejunctional on nerve
organs endings (α2A), also post
junctional in brain, pancreatic
β-cells, platelets &
extrajunctional in certain
blood vessels
2. Selective agonist Phenylephrine, methoxamine Clonidine
3. Selective antagonist Prazosin Yohimbine, rauwolscine

Characterization of Adrenergic Receptors (Fig. 1.4)


Adrenoceptors are the members of a receptor superfamily of membrane spanning proteins
including muscarinic, serotonin & dopamine receptors. These are coupled to intracellular GTP-
binding proteins (G-protein). These receptors have a single polypeptide chain, looped back &
forth to cell membrane, sometimes with an extracellular N-terminus & intracellular C-terminus.
The seven transmembrane domains TMD1-TMD7 are composed primarily of lipophilic amino
acids arranged in α-helices connected by regions from loops on the intracellular & extracellular
faces of the membrane. The recognition sites for agonist/antagonists are located with the
membrane bound portion of the receptor. The binding site is located within a pocket formed by
the membrane-spanning region of the peptide.
All of the adrenoceptors coupled to their effectors system through G-protein, which is linked
through reversible binding interactions with third intracellular loop of the receptor region.
Actually, cytoplasmic region of the receptor interact with G-protein. Specifically, Asp113 in
TMD-3 of β2-receptor, an acidic residue that forms a bond (presumably ionic bond or a salt
bridge), with the positively charged –NH2 group of CA agonist. Ser204 & Ser207 of TMD5 form
hydrogen bond
Table 1.5: Effects mediated by adrenoceptors subtypes

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Adrenergic & Anti-Adrenergic Drugs
Predominantly α-receptors
(a) Medulla oblongata (α2) Reduction of BP & HR
(b) Blood vessels (α1)
Skin & mucosa Constriction
Cerebral Constriction (slight)
(c) Skin (α1)
Pilomotor muscle Constriction
Sweat gland Slight constriction
(d) Radial muscles of iris (α1) Constriction (mydriasis)
(e) Salivary glands except parotid Thick, viscous secretion
(f) Sex organ, male Ejaculation
Predominantly β-receptors
(a) Heart (β1, α1)
SA node (β1) Increased HR (positive chronotropic)
Atria (β1) Increased contraction (positive inotropic)
AV node (β1) Faster conduction
Ventricles (β1) Increase contractility & conductivity, increased
automaticity (positive dromotropic)
(b) Bronchial muscles (β2) Relaxation
(c) Skeletal muscle changes (β2) Changes in contractility
(d) Skeletal muscle blood vessels (β2) Dilatation
Both α & β-receptors
(a) G. I. Tract
Motility & tone (α2, β2) Deceased
Sphincter (α) Contraction
Pancreas
α2 Inhibition of insulin secretion
β2 Stimulation of insulin release, glucagons secretion
(b) Urinary bladder
Trigone (α) Contraction
Detrusor (β) Relaxation

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(c) Blood vessels
Coronary (α1, β2) Constriction, dilatation
Pulmonary (α1, β2) Constriction, dilatation
Abdominal viscera (α1, β2) Constriction (mainly), dilatation
Renal (α1, β2) Constriction, dilatation
Skeletal muscle (α1, β2) Constriction, dilatation
(d) Adipocytes
α2 Inhibit lipolysis
β3 Lipolysis
(e) Liver (α1, β2) Glycogenolysis, neoglucogenesis, inhibition of
glycogen synthetase
(f) Uterus
α1 Stimulation
β2 Inhibition
(g) Leukocytes (β2) Inhibits chemotaxis & lysosomal enzyme release
(h) Platelets (α2) Platelet aggregation
(i) Kidney (mainly β1) Rennin release
(j) Posterior pituitary (β1) ADH secretion
(k) Mast cells (β2) Inhibition of mast cells
(l) Nerve terminals
Adrenergic (α2, β1) Decrease release, increased release
Cholinergic (α2) Decrease release

with catechol meta & para-hydroxyl group, respectively of adrenergic agonist, while β-hydroxy
group of adrenergic agonist form hydrogen bond with side chain of Aspragine 293 in TMD6 &
Phe290 interact with catechol ring. A disulphide bond is existing between Cys106 & Cys184 in

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TMD4. Third intracellular loop connecting TMD5 & TMD6 is the site of linkage between
receptor & its associated G-proteins.
Effector Mechanism of NH2

VII
Adrenoceptors VI

The adrenergic receptors, each are


coupled through the G-proteins to
HO
the effector mechanism. Effector
OH
mechanisms are proteins that are I V
OH
able to translate the conformational +
NH3
changes caused by activation of S
S

receptor into a biochemical event. II


IV
β-Receptors (Fig 1.5)
III
All the three β-receptors are coupled
S
via specific G-protein (Gs) to the S
COOH
activation of adenlyl cyclase, which
Fig 1.4: Binding sites for epinephrine on adrenergic
catalyzes the conversion of ATP into
receptor
camp. GDP binds reversibly with Gs
protein in absence of agonist.
Interaction of agonist to the receptor leads to conformational changes in Gs-protein, causing
decrease in its affinity for GDP with concomitant increase in affinity for GTP. GTP binds to αS-
subunit of Gs-protein, dissociates from receptor G-protein ternary complex & binds to &
activates adenylyl cyclase. The bound GTP is, then, hydrolyzed to GDP & the receptor-Gsprotein
complex returns to the basal state.
Intracellularly, secondary messenger cAMP activate protein ‘kinase’, which phosphorylates
specific proteins responsible for specific pharmacological actions. A class of enzymes known as
“phosphodiesterase”, which hydrolyse cAMP to AMP, terminating the action of cAMP.
Binding of adenylyl cyclase requires Mg++ complex in inner membrane of cell, which can be
inhibited by a number of nucleoside triphosphates & their analogs. They inhibit adenylyl cyclase
at Mg-ATP binding site. Other inhibitors include divalent inorganic ions, Li+, F- etc.
prostagladins PGE1 & PGE2 also stimulate adenylyl cyclase. Activation of phosphodiesterase

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Adrenergic & Anti-Adrenergic Drugs
requires Ca++, so EDTA may inhibit the action of PDE. Other inhibitors include xanthines
(specially theophylline) & 1-methyl-3-isobutyl xanthine (MIX). Overall cascade is drawn in Fig.
1.5.
α-Receptors
Both the subtypes (α1 & α2) also belong to the superfamily of membrane receptors coupled with
G-proteins. The α1-adrenergic
β) (
Agonist + Receptors
receptor is coupled
‘Phospholipase C’ (PC) via
Activation of sG
-proteins
Gq-protein. PC hydrolyses

Affinity for GDP decreases, phosphatidyl inositol-1,4,5-


Affinity for GT P increases triphosphate (PIP3) to
secondary messengers
-protein at itsα s-subunit
G TP bound to sG inositol-1,4,5-triphosphate
GTP
(IP3) & 1,2-diacylglycerol

GDP (DAG). IP3 (water soluble)


stimulates the release of Ca++
Activation of adenyl cyclase
from sarcoplasmic reticulum,
while DAG (lipid soluble)
NH2
NH2
NH2 activates ‘protein kinase C’
N
N N
N
PD E N
N (pKC), an enzyme that
O N N
HO
O
O
O
O O O
O
O
N N
O N N phosphorylates proteins.
P O HO O O
P P P
OH OH OH
OH
P
α1-adrenergic receptor
OH
HO OH
O OH
HO OH activation also increases
ATP cAM P AM P extracellular Ca++ influx via
voltage dependent as well as
stimulate "K inase"
non-voltage dependent Ca++
channels. (Fig 1.6)
Phosphorylates many proteins
α2-adrenergic receptors are
Fig 1.5: Effector mechanism of action of β-receptors coupled with Gi-protein,
which on activation by α2-

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
adrenergic agonists inhibits adenylyl cyclase leading to decrease in intracellular cAMP level.
Thus, activity of α2-adrenergic receptors is just opposite to that of β-receptors.

α-Agonist

α1-Adrenoceptors α2 −Adrenoceptors

Stimulation of G q-proteins Stimulation of G i-protein

Coupling to enzyme phospholipase C Decrease activity of


adenylyl cyclase

PIP3 IP3 + DAG Decrease level of cAMP

Activation of protein kinase C


Release of Ca ++ from
sarcoplasmic reticulum

Phosphorylation of protein
Response
Response
Fig 1.6: Effector mechanism of α-adrenocerptors

Design of Drugs affecting Adrenergic Nervous System (Fig 1.7)


The multiple sites involved in activation of adrenergic nervous system suggest several
approaches to design the drugs to control its action. Among these are
1. Drugs that affect the biosynthesis of CAs.
2. Drugs that affect storage & release of CAs.
3. Drugs affecting the receptors i.e. agonists & antagonists.
4. Drugs affecting metabolism &/or removal of CAs from areas surrounding the
receptors.
5. Drugs affecting the postsynaptic regulation of hormone action.

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Adrenergic & Anti-Adrenergic Drugs

Tyrosine
- α-Methyltyrosine
MAO
NA Methyldopa
Metabolites synthesis
- PRESYNAPTIC
MeNA NEURON
MAOI NA
Reserpine -
-
α2-receptors
MeNA
NA
Uptake 1
α2-agonists NA
Uptake 2 inhibitors
α2-agonists
antagonist
- - -
Uptake 2

-
β α

α-antagonists
β -antagonists
POSTSYNAPTIC CELL

Fig 1.7: Different biochemical sites for drug action in adrenergic nervous system

Drugs affecting CA biosynthesis


Metyrosine: It is α-methyl derivative of tyrosine. It is a competitive inhibitor of tyrosine
hydroxylase, the first & rate limiting step of CA biosynthesis. However, it is used as a racemic
mixture. (-) isomer [posses inhibitory activity. It is used in NH2
COOH
pre-operative management of pheochromocytoma. The
drug is excreted mainly unchanged in urine, due to very
CH3
HO
low solubility in water. Crystalluria is a potential side
Metyrosine
effect. It is supposed to be ideal drug for biosynthetic
inhibition of CAs.

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Aromatic amino acid decarboxylase (step 2) may is
inhibited by α-methyldopa & carbidopa. Actually,
carbidopa acts a as substrate for enzyme & is effective inhibitor because its rate of
decarboxylation is too much lower than that of methyldopa.
Dopamine hydroxylase can be inhibited by disulfiram (an antabuse) has non-specific action on a
number of oxidative enzymes. It is used in alcohol withdrawal due to having inhibitory activity
alcohol dehydrogenase.
CH3
CH3
HO COOH
HO COOH S S

NEt2 HO HN
HO H2N Et 2N S S NH2

α-Methyldopa Disulfiram Carbidopa (Sinemet)

Drugs affecting storage & release of CAs


Since stimulation of adrenergic system requires the release of NE (& other CAs) from its storage
sites & then from the neuron. Compounds affecting this release may effectively control organs
innervated by ANS.
Cocaine & reserpine deplete NE, epinephrine & serotonin from sites of storage. Reserpine
binds tightly to ATP driver monoamine transporter, leading to blockage of transport of CAs form
cytoplasm to storage vesicles. Thus, CAs are not released but metabolized by MAO. Reserpine is
metabolized by hydrolysis of ester functional group at position 18. it is used in the treatment of
hypertension. Diuretics, usually increases the efficacy of reserpine. Cocaine interferes with NE
uptake at neurons leading to increase in NE concentration at receptor.

N COOCH 3
H3CO N H
H H
O OMe NMe O
H

H 3COOC O OMe O
OCH 3
OMe

Reserpine Cocaine

Guanethidine & Guanadrel are neuronal blocking agents that prevent release of NE from

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
sympathetic terminals. These drugs enter in uptake 1 & accumulate in neuronal storage vesicles,
where they stabilize neuronal storage vesicle membrane & make them less responsive to nerve
impulse. In these compounds, a guanidine moiety [NHC(=NH)NH2] is attached to either an
alicyclic or aromatic lipophilic group. Due to presence of very basic guanidine group (pKa > 12)

NH

NH NH2 O NH NH2
N

NH O
Guanethidine Guanadrel
(1-[2-(azocan-1-yl)ethyl]guanidine) (1-(1,4-dioxaspiro[4.5]dec-2-ylmethyl)guanidine

these compounds are protonated at physiological pH, so these are unable to cross blood brain
barrier. Guanethidine is absorbed incompletely after oral administration (3-50%) while guanadrel
is well absorbed (bioavailability 85%). -
SO 3
Guanethidine has half-life of 5 days, while CH3
guanadrel has 12 hours. Both are partially N
+
CH3
metabolized by liver. Both the drugs are
CH3
used as antihypertensive.
Br
CH3
Bretylium tosylate (Bretylol) is another
1
neuronal blocking agent containing Bretylium tosylate
aromatic quaternary ammonium moiety &
used as antiarrythymic agent.

Drugs Affecting Adrenoceptors i.e., Agonists & Antagonists


Adrenoceptor Agonists (Sympathomimetics)
Sympathomimetic agents produce effects resembling those produced by stimulation of
sympathomimetics nervous system. they may be classified as follow:
1. Direct acting sympathomimetics elicit sympathomimetic response by interacting
directly with adrenergic receptors.

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Adrenergic & Anti-Adrenergic Drugs
2. Indirect acting sympathomimetics produce adrenergic effects by causing release
from adrenergic nerve terminals, but they do not act directly.
3. Mixed mechanism of action is also shown by some drugs.
(A) Direct Acting Sympathomimetics
The parent structure of many of the sympathomimetics is β-phenylethylamine.

meta β NH2

para

In general, for agonistic activity at adrenergic nerve, these are essential conditions:
(1) A phenylethylamine structure
OH
(2) A 3-hydroxy substitution on the ring,
NHR1
preferably a 3,4-dihydroxy substitution 2'
1 2
3'
(catechol) on the ring. 1'
R3
(3) A β-hydroxyl group with proper 4' 6'
R2
steric configuration at that position. 5'

(4) A small substitution (H, CH3, CH2CH3)


may be placed on the catechol without Ser204
p
affecting agonist activity.
(5) The nitrogen atom must have atleast one
OH
hydrogen. Ser267
OH
OH
Stereochemical Aspects
OH
Direct acting sympathomimetics that exhibit
chirality by virtue of the presence of a β-
NH2
hydroxyl group (phenylethanolamine) H

OH O
invariably exhibit high stereoselectivity in H Asn293
H
producing their agonistic effect i.e. one
enantiomer is more potent than other +
NH3
enantiomer. In NE & related compounds,
CO2-

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Fig 1.8 : Easson-Stedman hypothesis
Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
enantiomer having (R)-configuration is
about 100 times more potent than (S)-
enatiomer. It is assumed for all the directly acting β-phenylethylamine derivatives structurally
resembling to NE, the more potent enantiomer should have conformation that results in
arrangement in space of the catechol group, the amino group & β-hydroxyl group in a fashion
resembling that of R(-)NE. This explanation of stereochemistry of NE is known as Easson-
Stedman Hypothesis, which is based on the presumed interaction of these three critic
pharmacophoric groups with three complementary binding areas on the receptors. (Fig 1.8)

Structure-Activity-Relationships of β-phenylethylamine derivatives


OH
NHR1
2'
1 2
3'
1'
R3
4' 6'
R2
5'

(I) R1, Substitution on Amino Nitrogen atom


The presence of amino group in phenylethylamines is important for direct activity. The
amino group should be separated from aromatic ring by two carbon atoms for optimal
activity. Both primary & secondary amines found in potent direct acting agonists, but tertiary
amino group reduce activity.
1) As the bulk of substitution on N-atom increases, the affinity for α-receptor
decreases & for β-receptor increases. For example, NE having hydrogen at N-atom is a
potent β1-agonist & α-agonist, epinephrine having methyl group at nitrogen atom is potent α,
β1 & β2 agonist & isoproterenol having isopropyl group on nitrogen atom is a potent β1 & β2
agonist.
OH OH
OH

NH(CH3)2 HO NHCH(CH3)2
HO NHCH3 HO

HO HO
HO

Norepinephrine Epinephrine Isoproterenol

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Presumably, the β-receptor has a large lipophilic binding pocket adjacent to the amine
binding asparatic acid residue, which is absent in α1-receptors. If R1 becomes larger than
butyl group, than intrinsic activity is lost & then, respective compound becomes α 1-blocking
activity. e.g. labetalol.
OH

H2NOC NH

CH3
HO
Labetalol

2) N-substitution provides the selectivity for different β-receptors, like N-tert-butyl


substitution enhances the β2-selectivity. e.g. N-tert-butylnorepinephrine (Colterol), prodrug is
bitolterol, is 9-10 times more potent at bronchial β2-receptors than cardiac β1-receptors. Large
lipophilic substitution on N-atom enhances β2-selectivity. e.g. formoterol, salmeterol,
ritodrine etc.
CH3

O OH
H3C O
O HO NHC(CH3)

O
NHC(CH3)3 HO

OH
Bitolterol Colterol

3) Large substitution on N-atom gives MAO resistant compounds.

(II) R2 substitution, α to the basis nitrogen, Carbon 2


1) small ethyl or methyl substitution on α -carbon of the ethylamine side chain reduces the
direct receptor agonist activity at both α - & β - receptors. Such substitutions slow
metabolism by MAO. Such compounds often exhibit enhanced oral effectiveness & greater
CNS activity.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
2) An α -ethyl group diminishes α -activity for more than β -activity affording the
compounds as ethylnorepinephrine & isothrine, a selective β 2-agonist, while methyl
substitution at this position favors α 2-selectivity like α -methylnorepinephrine &
methyldopa.

OH OH
HOOC
NHCH(CH3)2 HO NH2
HO NH2 HO

C 2H 5 CH3
CH3
HO HO
HO

α-methylnorepinephrine Isotherine Methyldopa


(α2-agonist) (β2-agonist weaker than isopropranolol) (α2-agonist)

3) Another effect of α -substitution is the introduction of new chiral center, which has the
pronounced effects on the stereochemical requirements for activity. For example, with α -
methylnorepinephrine, it is erythro (1R,2S) isomer that possesses significant activity at α 1-
receptors.
H OH

HO NH2

H3C H
HO

(1R,2S) methylnorepinephrine direct acting isomer

(III) R3, substitution on the aromatic ring


1) The natural 3’,4’-dihydroxy (catechol) subtitution ring provides excellent α &
β receptor activity, but catechol containing compounds have poor oral activity because they
are hydrophilic & readily oxidized by COMT & MAO.
2) 3’,5’-dihydroxy (resorcinol) substitution forms such compounds, which are not substrate
for COMT as well as MAO & have longer duration of action, good oral activity & better
selectivity at β 2-receptors. e.g. resorcinol substitution in isoproterenol in place of catechol
produces metaproterenol, a β 2-agonist. Another example on such compounds is terbutaline.
Metabolism of these compounds usually occurs by glucuronide conjugation.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
OH OH

NHCH(CH3)2 NHC(CH3)3
HO HO

OH OH
resercinol ring provides
β2-receptor selectiv ity Metaproterenol Terbutaline

3) Replacement of meta-hydroxyl group of catechol structure with a hydroxymethyl group also


provides β 2-receptor agonist. E.g. albuterol (salbutamol), salmeterol, pirbuterol (having pyridine
ring in place of phenyl ring). Theses compounds are also COMT & MAO resistant & possesses
better oral activity.

Hydroxymethyl substitution provides better β2-selectivity

OH OH

NHC(CH3)3 HOH2C NHCH2(CH2)5O(CH2)4Ph


HOH2C

HO HO

Albuterol(Salbutamol) Salmeterol
OH

HOH2C N NHC(CH3)3

HO
Pirbuterol

4) Removal of p-hydroxy group from epinephrine provides phenylehrine, a selective α 1-


agonist.i.e. removal of 4’-hydroxy group eliminates the β -activity. Another example is
Metaraminol.
5) Removal of meta-hydroxyl group results in selective β 2-receptor agonist like ritodrine
(Yutopar), Isoxsurpine & nylidrine.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs

Removal of m-hyroxyl group enhances β2-agonist activity


OH
OH
OH
NH
NH
NH
O CH3
CH3
CH3 CH3
CH3 HO
HO OH HO

Ritodrine Isoxurpine Nylidrine

6) 2’,5’-dihydroxy substitution in aromatic ring shows the selectivity for α -receptors. e.g.
Metoxamine, a selective α 1-agonist, but at higher concentrations it may exhibit β -blocking
activity. Another example include Midodrine.

2',5'-dihydroxy/methoxy substitution afffords α1-agonist acivity

OCH 3 OH
OCH 3 OH
NH2
NH
NH2
CH 3
O

H 3CO H 3CO

Methoxamine Midodrine

(B) Indirect Acting Sympathomimetics


Indirect acting sympathomimetics act by releasing endogenous norepinephrine. They enter the
nerve ending by the way of active uptake process & displace norepinephrine from its storage
granules. Certain structural characteristics tend to impart indirect sympathomimetic activity.
Some of them are following:
1) Like direct acting sympathomimetics, presence of catechol hydroxyl group enhances the
potency of indirect acting phenylethylamines, but is not mandatory.
2) The presence of β -hydroxyl group decreases & α -methyl group increases the
effectiveness of indirect acting sympathomimetics. e.g. amphetamine, S(+) enantiomer is
used.
3) The presence of nitrogen substitution decreases the activity, while the substitutions larger
than methyl group rendering the compound inactive. Compounds with N-methyl group are
orally well active since they are MAO resistant. e.g. Mathamphetamine
4) Presence of tertiary amino group makes the compound inactive.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
5) Phenyl moiety can be substited with either aromatic or cycloalkyl group e.g.
Propylhexedrine (Benzdrex), Tazolol. Propylhexdrine is used as a vasoconstrictor & nasal
decongestant.
OH
NH2 NH2
NHCH 3
N O NHCH(CH3)2

CH3 CH3 CH3


S

Methamphetamine Tazolol Amphetamine Propylhexedine

Other indirect acting sympathomimetics include Hydroxyamphetamine (Peredrine) & α -


methyl derives of p-tyramine. Hydroxyamphetamine is used to dilate the pupil of eye for
diagnostic eye examination. It has some atropine like anticholinergic actions like mydriasis.
(C) Sympathomimetics with mixed mechanism of action
Ephedrine has mixed mechanism of action. The basic difference in activity is due the
stereochemistry of the carbons possessing β -hydroxyl group & methyl group (carbon 1 &
carbon 2 respectively). Due to two chiral atoms in ephedrine, there may be four enantiomer of
ephedrine. Racemic mixture of erythro (D) pair of enantiomer is known as “ephedrine”, whereas
racemic mixture of threo (L) pair of enantiomer is known as pseudoephedrine (ψ -ephedrine).
This drug is obtained from alkaloids of Ephedra spp. Natural ephedrine is D (-) isomer having
(1R:2S) configuration & is the most active in all the four isomers, (1S:2R) enantiomer i.e. D (+)
ephedrine & (1S:2S) enantiomer i.e. L (+) pseudoephedrine usually have the indirect activity
& (1R:2R) enantiomer i.e. L(-) pseudoephedrine is inactive.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
OH OH

NHCH3 NHCH3

CH3 CH3

(1R,2S), D(-)ephidrine (mixed action) (1S,2R), D(+)ephidrine (indirect active)


Erythro pair of enantiomer ''ephidrine''

OH OH

NHCH3 NHCH3

CH3 CH3

(1R,2R), L(-)pseudoephidrine (inactive) (1S,2S), L(+)pseudoephidrine (indirect active)


Thereo pair of enantiomer ''pseudoephidrine''

(1R:2S)D(-) ephedrine & (1S:2S)L(+) pseudoephedrine are not metabolized by MAO & COMT,
but they are p-hydroxylated & N-demethylated by CYP450 mixed function oxidase. Ephedrine
decomposes gradually & darkens when exposed to light. It is a strong base, pH >10.
Phenylpropanolamine (Propadrine) is similar to OH
ephedrine in structure except it has terminal primary
NH2
amine in place of secondary amine as in ephedrine. This
CH3
modification gives an agent that has higher vasopressive
Phenylpropanolamine
action & lower central stimulatory action than ephedrine. 2-amino-1-phenylpropan-1-ol

It is better nasal decongestant than ephedrine. It is orally active also.

OH Metaraminol (Aramine): 3-(2-amino-1-hydroxypropyl)phenol


NH2 It is structurally similar to phenylephidrine except it has terminal
primary amine & possess direct action on α-adrenergic neurons. It
CH3
is used parenterally as vasopressive in the treatment & prevention
OH of acute hypotensive state occurring with spinal anesthesia.
Metaraminol

Description of Sympathomimetics
(A) Endogenous catecholamines

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Dopamine: Three natural occurring catecholamines are dopamine, norepinephrine &
epinephrine along with norepinephrine & epinephrine used in the treatment of shock. It enhances
blood flow to kidney, enhancing glomerular filtration rate, Na+ excretion & inturn increases urine
output. The dilation of blood vessels produced by dopamine is the result of agonistic action on
D1-receptors. Dopamine also stimulates cardiac β1-receptors to increase cardiac output.
Dopamine intravenous (>10μg/kg/min) stimulates α1-receptors, leading to vasoconstriction & an
increase in arterial blood pressure.
Norepinephrine (Levophed): It has also poor oral bioavailability & is a good substrate for
MAO & COMT. Rapid metabolism causes short duration of action. It is used to maintain blood
pressure in acute hypotension resulting from surgical or surgical trauma, central motor
depression & hemorrhage. It is given intravenously.
Epinephrine (Adrenaline): It has stimulatory effects on both α- & β-receptors. Like other
catecholamines, it is also light sensitive because of catechol ring system. pink colour indicates
the presence of oxidative breakdown. It is inhibited by antioxidant like NaHSO3. as a free amine,
it is used as aqueous solution for inhalation. It is rapidly destroyed by alkaline solutions, metals
(Ca, Fe, Zn etc.), weak oxidizing agents & aerial oxygen.
Dipivefrin (Dipivalyl epinephrine, propine): It is prodrug of epinephrine that is formed by
esterification of catechol hydroxyl groups with pivalic acid. It is more lipophilic than
epinephrine, so it has more oral bioavailability. It penetrates eye better (so used in open angle
glaucoma) & reduces the doses w.r.t. Epinephrine. In cornea & anterior chamber, it is broken
down into epinephrine by esterase & it is less irritant than epinephrine.
OH
OH
NHCH3
NHCH3 HO
(H3C)3COCO Esterase in anterior
chamber & cornea
CH3 + 2(CH3)3CCOOH
CH3
HO
(H3C)3COCO
Dipivefrin Epinephrine Pivalic acid

(B) α1-Adrenergic Receptor Agonists


Phenylephrine (Neo-synephrine): 3-[1-hydroxy-2-(methylamino)propyl]phenol
Removal of 4’-OH group from phenylethylamine structure eliminates β-activity & enhances α1-
activity. Phenylephrine is a prototype drug for α1-agonists. OH

HO NHCH3

CH3
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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
It is more potent vasoconstrictor than epinephrine &
norepinephrine. Oral bioavailability is good, it is
metabolized by MAO only, not by COMT due to lack of
catechol ring.
It is non-toxic & crosses blood brain barrier. It is used as nasal decongestant & to dilate the pupil
(in treatment of open angle glaucoma). It is also used in spinal anesthesia, to prolong anesthesia
& to prevent a drop in blood pressure during anesthesia.
Methoxamine (Vasoxyl): 2-amino-1-(2,5-dimethoxyphenyl)propan-1-ol
It is selective direct agonist. This drug is not substrate for COMT, OH
OCH3
duration of action is longer than norepinephrine & is bioactivated
NH2
by O-demethylation to an active m-phenolic compound. It is
primarily used during surgery to maintain the adequate arterial BP, CH3

especially in conjunction with spinal anesthesia. It does not OCH3

stimulate CNS.
Midodrine (Proamatine): 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide
It is N-glycyl prodrug of α1-selective agonist desglymidodrine. It is used as a vasoconstrictor in
the treatment of hypotension.
(C) α2-Receptor Agonists
Methyldopa (Aldomet): it is a prodrug of NE, which is not given as drug. Methyldopa (L-α-
methyl-3,4-dihydroxyphenylalanine) is a close structural analog of L-dopa & is a substrate for
the enzyme, L-aromatic amino acid decarboxylase. Methyldopa is converted into α-
methylnorepinephrine having (1R, 2S) configuration & acts selectively on α2-adrenoceptors in
CNS as same manner as clonidine.
OH

HO HO HO NH2 HO NH2
NH3Cl NH2 L-aromatic amino DA-β-hydro-
Esterase
CO 2Et CO 2H H 3C H xylase H 3C H
H3C H3C acid decarboxylases HO HO
HO HO

Methyldopate Methyldopa α-Methyldopamine (1R,2S)-α-Methyl NE

Bioactivation of methyldopa

Due to more hydrophilicity, they (α-methyldopa & α-methylnorepinephrine) are unable to cross
blood brain barrier. Α-Methylnorepinephrine replaces norepinephrine at the nerve terminals & it
has the intrinsic activity, so it can act as false neurotransmitter. It also decreases concentration of

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
dopamine, epinephrine & serotonin in CNS & periphery. It also decreases sympathetic outflow
& BP.
Methyldopa is used only by oral administration since its zwitterionic character limits its
solubility. Absorption can vary from 8-62% & appear to involve an amino acid transporter.
Absorption is affected by food & about 40% of absorbed methyldopa is converted to
methyldopa-O-sulphate by mucosal intestinal cells. Entry into CNS also appears to involve an
active transport process. The ester hydrochloride salt of methyldopa, methyldopate (Aldomet
ester) was developed as a highly water soluble salt that could be used to mask parenteral
preparations. Methyldopate is converted to methyldopa in the body through the action of
esterase.
(D) Imidazoline derivatives, α-agonists
In addition to β-phenylethylamine class of adrenergic receptor agonists, there is a second
chemical class of compounds viz. imidazolines. These imidazolines may be non-selective or may
be selective for either α1 or α2-adrenergic receptors. Structurally, imidazolines for the most part
have the heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type
of bridging unit.
N
Ar X
N
Aromatic H
Bridging
moiety unit Imidazoline
ring

SAR of α-agonist imidazoline


Structure-Activity-Relationship of imidazoline α-agonist can be explained by following points:
1. The optimum bridging unit (X) is usually a single amino or methylene
group e.g. clonidine (having amino bridge for α2-activity), oxymetazoline & xylometazoline
(having methylene bridge for α1-activity).

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
CH3
Cl N
N
NH N
NH
NH
NH CH3
Cl (H3C)3C
HO
Clonidine Naphazoline Oxymetazoline

2. Agonistic activity at α1- & α2-receptors is enhanced when aromatic ring


is substituted with halogen atom like chlorine or small alkyl group (lipophilic substitution)
like methyl particurly when they are placed in two ortho positions e.g. clonidine.
3. Bulky lipophilic groups attached to the phenyl ring at meta or para
position provide selectivity for α1-receptors by diminishing affinity for α2-receptors.
2-Arylalkylimidazolines (α1-agonists)
These include naphazoline (Prinine), tetrahydrozoline (Tyzine, Visine), xylometazoline
(Otrivin) & Oxymetazoline (Afrin) are agonists at agonists at α1-adrenoceptors & α2-
adrenoceptors. These agents are topically used for their nasal decongestant & for their
vasoconstrictive effect. They have limited access to CNS, since they essentially exist in an
ionized form at physiological pH, because of very basic nature of imididazoline ring (pKa 9-10).
N N

N N N
N H H
H3C CH3 H3C CH3
N N
H H

OH
CMe 3 CMe 3

Naphazoline Tetrahydrozoline Oxymetazoline Xylometazoline


2-(naphthalen-1-ylmethyl)-4,5-dihy- 2-(5,6,7,8-tetrahydronaphthalen-1-yl 6-tert-butyl-3-(4,5-dihydro-1H-imidazol 2-(4-tert-butyl-2,6-dimethylbenzyl)
-dro-1H-imidazole -methyl)-4,5-dihydro-1H-imidazole -2-ylmethyl)-2,4-dimethylphenol -4,5-dihydro-1H-imidazole

2-Aminoimidazolines (α2-agonists)
Clonidine: N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
It is the prototype drug of this class & these are selective α 2-agonists. These have some α1-
agonistic activity (vasoconstriction) in periphery. They also act on imidazoline (I1) receptors* in
CNS to control BP (decrease BP). BP may increase at initial due to peripheral α 1-agonistic
activity. It crosses blood brain barrier & interact with α 2-receptors in CNS (nucleus tractus
solitarius region in brain).
Similar to imidazoline α1-agonist, clonidine has lipophilic ortho-substituents on phenyl ring. The
ortho-chlorine groups afford better activity than ortho-methyl groups at α2-receptors. Presence of

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
amino group makes the imidazoline ring part of a guanidine group & uncharged form of
clonidine exists as a pair of tautomers. Actually, in case of clonidine, basicity of guanidine group
(pKa 13.6) is decreased to pKa 8.0, because of its direct attachment to the ortho-dichlorophenyl
ring. Thus at the physiological pH, clonidine exist in non-ionized form (20%) required for
passage into CNS.
One of the metabolite of clonidine, 4-hydroxyclonidine is the active α 2-agonist but poor
hypotensive. Clonidine mainly acts on α2A-receptors. The positive charge is shared through
resonanmce by all three nitrogen atoms of the guanidine group. Steric crowding by the bulky
ortho-chlorine does not permit a coplanar conformation of two rings.
Cl Cl H Cl
N N N NH N
NH

NH NH NH
Cl Cl HO Cl

Clonidine (t1/2=20-25 hrs) 4-Hydroxyclonidine

*Dexmedetomidine & moxonidine are selective I1-agonists used as antihypertensive.


CH3 CH3 OCH 3
H N
H3C NH
N
N
N
N Cl H
H3C N
Dexmedetonidine Moxonidine
5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6
-methoxy-2-methylpyrimidin-5-amine

Apraclonidine (Iopidine) & brominidine are selective α2-agonist. They are used to lower
intraocular pressure by reducing aqueous humor production & increasing its outflow.
Apraclonidine is also used to control elevation in intraocular pressure that can occur during the
laser surgery of the eyes. Brimonidine is more active than clonidine. Tizanidine (Zanaflex), by
stimulating α2-receptor, decreases the release of excitatory amino acid neurotransmitter from
spinal cord interneurons. So, it is used in treating spasticity associated with sclerosis or spinal
cord injury.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Cl N Cl
N
NH N N Br
N N
NH H
NH N N
Cl NH H S N
H2N

Apraclonidine Brimonidine Tizanidine


2,6-dichloro-N1-(4,5-dihydro-1H-imidazol-2-yl) 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl) 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)
quinoxalin-6-amine -2,1,3-benzothiadiazol-4-amine
benzene-1,4-diamine

Guanabenz (Wytensin) & Guanafacine (Tenex) are clonidine derivatives, used as


antihypertensives. Structurally, they can be considered as “open ring imidazolines”. These
compounds have 2,6-dichlorophenyl moiety, found in clonidine, connected with guanidine group
by a two atom bridge. Guanidine group decreases the pKa, due to which, a significant portion of
these drug may exist in non-ionised form at physiological pH. Their machanism of action is same
as that of clonidine.
Cl
Cl
NH NH2 NH NH2
N

NH O
Cl NH
Cl

Guanabenz Guanafacine
2-(2,6-dichlorobenzylidene)hydrazinecarboximidamide N-carbamimidoyl-2-(2,6-dichlorophenyl)acetamide

(E) Dual α- & β-Adrenergic Receptor Agonist


Dobutamine (Dobutrex): It is structurally 1-(methyl)-3-(4-hydroxylphenyl)propyl derivative at
amino group of dopamine. The racemic (±) dobutamine has OH

direct activity on both α1- & β1-receptors, (+)enantiomer is HO NH

potent full agonist at both β1 & β2-receptors. The S(-)


HO CH3
enantiomer exhibit β1-agonistic activity & also a powerful
Dobutamine
α1-agonist & vasopressor. Dobutamine is used as a cardiac 4-(2-{[4-(4-hydroxyphenyl)butan-2-yl]amino}
ethyl)benzene-1,2-diol
stimulant after surgery or CHF. It is metabolized by COMT
& conjugation, but not by MAO.

(F) β-Adrenergic Receptor Agonists


Isoproterenol: 4-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-1,2-diol
SAR reveals that due to presence of isopropyl group at N-atom diminishes the α 1-activity. It acts
only on β1 & β2-receptors.
OH CH3

HO NH
CH3

- 30 - HO
Isoproterenol
Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
It shows cardiac stimulant action by β1-stimulation, while
β2-stimulation leads to bronchodilatation. It is potentially
used in bronchospasm, sometimes it is also used in heart
block. The oral absorption is erratic, duration of action is 1-
3 hours after inhalation. It is metabolized by sulfate & glucuronide conjugation & COMT, but
not by MAO. Due to presence of catechol, it is light sensitive. It is used in asthma & obstructive
pulmonary disease.
Metaproterenol & Terbutaline: These are resorcinol derivatives, so they are β2-agonists, lower
potent than isoproterenol, having loner duration of action due to no action of COMT & MAO.
Metabolism occurs by glucuronide conjugation. These are used in asthma.
OH OH

NHCH(CH3)2 NHC(CH 3 ) 3
HO HO

OH OH

Metaproterenol Terbutaline
5-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-1,3-diol 5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol

Albuterol, Pirbuterol & Salmeterol: due to replacement of m-OH group with hydroxymethyl
moiety, they are β2-agonists. Pirbuterol contains pyridine ring in place of phenyl ring. These re
not metabolized by MAO & COMT but conjugated by sulphate. They are orally active &
duration of action usually ranges from 3-6 hours. Salmeterol is partial agonist at β2-adrenoceptor
& has a potency similar to isoproterenol, longer duration of action (12 hours), due to lipophilic
phenylalkyl substitution on nitrogen atom.
OH OH
OH
NHC(CH 3 ) 3 NHC(CH 3 ) 3 NHCH2(CH2)5O(CH2)4C6H5

N
HO HO HO
CH2 OH CH 2 OH CH2OH

Albuterol (Salbutamol) Pirbuterol Salmeterol


4-[2-(tert-butylamino)-1-hydroxyethyl] 6-[2-(tert-butylamino)-1-hydroxyethyl]-
-2-(hydroxymethyl)phenol 2-(hydroxymethyl)pyridin-3-ol

Formeterol & levalbuterol: Formeterol is also OH

NH
another longer acting β2-agonist, which is associated
CH3 OCH3
with membrane lipid-bilayer for its action. It is used HO
NHCHO
Formeterol
N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-m ethoxyphenyl)propan-2-yl
am ino}ethyl)phenyl]form am ide

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
in asthma in conjunction with an inhaled
corticosteroids.
All the above β2-receptor agonists possess atleast one chiral center & are used as racemic
mixture.
Bitolterol (Tornalate): it is a prodrug of β2-agonist, colterol, N-tert-butyl analog og
norepinephrine. Presence of two p-toluic acid ester provides more lipophilicity than colterol,
makes it orally active. It is administered by inhalation for bronchial spasm & asthma. Bitolterol
has a longer duration of action (5-8 hours). It is metabolized by COMT after hydrolysis & by
conjugation.
OH OH
CH3
H3 C COO NHCMe3 NHCMe3
HO
Esterase

(Lung & other +


H3 C COO tissues) HO
COOH

Bitolterol Colterol p-toluic acid

Ritodrine (Yutopar): It is also selective β2-agonist, used to control premature labour & to
reverse fetal distress.
NH

CH3 OCH3
HO
Ritodrine
4-(2-{[2-(4-methoxyphenyl)ethyl]amino}propyl)phenol

ADRENERGIC ANTAGONISTS
β-Antagonists/β-Sympatholytics/β-Blockers
Basically, for antagonists structural changes should be done in such a way that they contribute to
affinity, but not to intrinsic activity. Structural prerequisite for β-antagonism is
phenethanolamine structure & a hydrophobic group (isopropyl or large) on nitrogen atom. To
eliminate intrinsic activity in a direct gent, the phenolic –OH of NE should be absent.
As in most antagonists, structures are larger than agonists & contain either substituted phenyl
groups, a naphthalene ring or heterocyclic ring system. An example of such compounds is

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
dichloroisopropterenol (DCI), in which N-isopropylphenethanolamine is retained for affinity,
but the phenolic –OH groups, required for intrinsic activity, have been replaced by Cl atoms.
Unfortunately, DCI was not a full agonist but a partial β-blocker.
Ethanolamines: In case of β-blocker, certain modifications can be made in the basic
isoproterenol structure to yield good β-blocking agent. These modifications include the
followings:
1. Replacement of catechol –OH groups with Cl atoms gives DCI.
2. N,N-disubstituted compounds are inactive.
3. Replacement of catechol-OH groups (electron rich –OH groups) with an electron rich
phenyl group (at 3,4-position) gives pronethalol, which is better β-blocker than DCI.
4. α-Methyl group decreases the activity.
5. Activity is maintained when phenylethyl, hydroxylethyl or methoxyphenylethyl groups
are added to the amine.
6. Cyclic alkyl substitutions on amine are better than corresponding open chain
substitutions.
OH
CH3
OH
CH3 OH CH3 NH
Cl NH
CH 3
NH
CH3 CH3

Cl H 3 CO 2 SHN

Dichloroisoproterenol (DCI) Pronethalol Sotalol

7. Chain length of an amine substituent may extend to a total of 4-carbon atoms without a
terminal phenyl.
8. Addition of an extra acrbon between naphthalene ring & amine decreases activity.
9. Changing from α to β position in naphthalene ring maintains activity.
10. Reduction of one ring to give either of two tetralin analog does not affect the activity.
11. Converting the aromatic portion to phenanthrene or anthracene is disadvantageous. It was
subsequently found that pronethanol derivatives caused lymphoids tumors in the mice. So,
concentration was diverted towards para-substituted ring. The prototype of this class is
methyl sulphonamide compound, sotalol. Meta-substituted rings do not afford good activity,
but substitution of methylsulphamido group with nitro group maintains the activity.

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Conceptual Medicinal Chemistry
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Aryloxypropanolamines: Naphthyloxypropanolamines were found to possess 10-20 times
greater activity than pronethanol & eliminates its carcinogenicity, provided that substitution was
at α-position rather than at β-position of naphthalene ring. Presumably, substution in this position
maintains the same spatial relationship as position maintain in phenylethanolamine series.
Propranolol is prototype drug of this chemical series. CH3
O
NH
An –OCH2- group is introduced in between aromatic ring & OH CH3

ethylamine side chain, but nature of aromatic ring & its


substituents are the primary determinant of β-antagonistic activity.
Propranolol
The nature of aryl group also affects the absortion, excretion &
metabolism of β-blocker.
Neither propranolol nor of its alkyl or alkoxy derivatives possess any agonistic activity. β-
Blockers with some agonistic activity are oxprenolol, alprenolol & practolol.
Structure-Activity-Relationship (SAR) of aryloxypropanolamines
OH CH3

O NH
CH3
R

1. Most derivatives of this series possesss various substituted phenyl rings rather than
naphthyl ring.
2. Substituton of CH3, Cl, OCH3 or NO2 group on the ring was favoured at position 2 & 3&
atleast at position 4.
3. When dimethyl substitution are made , 3,5-disubstituted compound (metiprolol) was best
& the 2,6 or 2,3,6-substituted compounds were least active. Presumably, this was due to
steric hindrance to rotation about the side chain.
4. Alkenyl or alkenyloxy groups in ortho-positin provided good activity. These compounds
can be considered ring open analog of propranolol. e.g. oxprenolol, alprenolol.
5. To eliminate the lipophilicity (which causes the penetration to blood brain barrier &
cardiac depressant action in addition to β-blocking activity) of propranolol, use of polar
methane sulphonamide was considered. The phenoxypropranolamine side chain was
retained, but the sulphonamide substituent was replaced with an acetamide substituent. This

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
gave rise to new compound, practolol, (a β1-blocker). In this new series, substitution on
either ortho- or meta- position resulted in loss of both potency & selectivity.
6. Like sympathomimetics, bulky aliphatic groups such as tert-butyl & isopropyl group are
normally found on the amino function. It must be secondary amine for optimal activity.
7. For selective β1-blocker, para- or 4-substitution along with absence of meta-substituents
in the phenoxypropanolamine moiety gives β1-blockers. Practolol (cardioselective antagonist)
is the prototype drug of this series. Exception is metiprolol (non-selective β-blocker).
8. Selective β2-blokers, like β2-agonists, they possess an α-methyl group, but the aromatic
hydroxyl group is generally replaced with other substituents. e. g. H35/25, metalol.
Stereochemistry of β-blockers
The β-blockers exhibit high stereoselectivity in the production of their β-blockling effects. As
with sympathomimetics, the configuration of the hydroxyl bearing carbon of the
aryloxypropanolamine side chain plays a critical role in interaction of β-blockers with β-
receptors. This carbon must possess (S) configuration for the optimal affinity to the β-receptors.
But, mostly β-blockers are used in racemic mixture. Only levobunolol, timolol & penbutolol
with (S) en, the –OH antiomer used. The structural feature of this aromatic portion of the
antagonist, however, appear to perturb the receptor or to interact with it in a manner that inhibit
activation. For phenethanolamines, the –OH group must occupy the same region as in adrenergic
agonists i.e. (R) configuration.
CH3 CH3
O O
NH NH
H CH3 HO H CH3
HO

(R) absolute configuration (S) absolute configuration

Non-Selective β-blockers
Propranolol (Inderal): It is the prototype drug for β-blockers. It is used for hypertension,
cardiac arrhythmias, angina pectoris, post myocardial infarction etc. It has membrane stabilizing
property (local anesthetic effect or quinidine like effect). Is is well absorbed after oral
administration, but it undergoes extensively first pass metabolism before it reaches the systemic
circulation. Metabolism usually involves N-dealkylation, deamination & oxidation. One
metabolite of particular interest is 4-hydroxypropranolol (a potent β-antagonist & has some

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
sympathomimetic activity). Main metabolite is naphthoxyacetic acid. Half-life of propranolol
after a single dose is 3-4 hours, which is increased to 4-6 hours after long-term therapy.
CH3 CH3
CH3
O O NH
NH CH3 O NH CH3
HO H CH3 OH OH CH3

O N
H
Propranolol O

Bunolol (Levobunolol) Carteolol

CH3
CH3
CH3
O O NH CH3
NH O NH CH3
H3C HO H CH3 O OH CH3
OH CH3
N
N

H3C N S
CH3
O CH3 S(-)Timolol (S)-Penbutolol
O

Metiprolol
CH3
CH3 CH3 O
NH
O NH CH3 O NH HO H CH3
CH3
HO OH CH3 OH

HO N OH
H
Nadolol
Pindolol 4-Hydroxypropranolol

Some non-selective β-blockers

Nadolol (Corgard) is used in long-term management of angina pectoris. Timolol (Timoptic,


Blocadren) finds its use in prophylaxis of migraine headache & the therapy following treatment
of myocardial infarction. Satolol is used as an antiarrythymic in treating ventricular arrythmias
& arterial fibrillation, in addition to its β-adrenergic activity. This agent can block the inward K +
current that display cardiac repolarization. Carteolol, timolol, levobunolol & metiprolol are
used topically in open angle glaucoma. These agents lower intraocular pressure with virtually no
effect on pupil size or accommodation. Presumably, they reduce the production of aqueous
humor. Through eye, systemic absortion may occur, producing adverse effects as bradycardia &
acute bronchospasm in patients with bronchospastic diseases. Pindolol possesses modest
membrane stabilizing activity & significant β-agonistic activity. Penbutolol & Carteolol also
have partial agonistic activity, cause less slowing of the resting heart rate than do agents without

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
this capability. The partial agonistic may be beneficial in patients who are likely to exhibit serve
bradycardia or who have little cardiac reserve.
Timolol, pindolol, penbutolol & carteolol have half-life values in the same range as propranolol.
The half life of nadolol is, however, about 20 hours, making it one of the largest acting β-
blockers. Timolol undergoes first pass metabolism but not to the same extent that propranolol
does. Timolol & penbutolol are metabolized extensively, with little or no unchanged drug
excreted in urine. Pindolol is metabolized by liver to the extent of 60% with the remaining 40%
being excreted in urine unchanged. Nadolol undergoes very little hepatic metabolism.
Selective β1-blockers
β-Blocking agents are very useful in treatment of cardiovascular disease like hypertension etc.
cardioselective β-antagonists are drugs with greater affinity for β1-receptors of heart than for β2-
receptors in other tissues. Such therapeutic agents provide two advantages, first, lack of β2-
antagonistic activity leads to no side effects on bronchioles, so making them safe for users
having bronchitis or asthma. Secondly, absence of vascular β2-receptors mediated vasodilatation
reduces or eliminates the increase in peripheral resistance that sometimes occur after
administration of non-selective β-antagonists.
CH3 CH3
O O NH
O NH
OH CH3 OH CH3
H3C
CH3
O NH
HN NH2 OH CH3
CH3

O O
O
Acebutolol Atenolol Betaxolol
CH3
O NH CH3
O CH3
OH CH3 NH O NH
OH CH3
OH CH3
O
O
O
H3C O
H3C CH3 H3C
O

Bisoprolol Esmolol Metprolol


Selective β 1-blockers

Atenolol (Tenormin) & metaprolol (Lopressor) are used in treatment of angina pectroris & in
therapy of myocardial infarction. Betaxolol (Kerlone, Betoptic) is only the β1-blocker used in
glaucoma. Acetobutolol (Sectral) & esmolol (Brevibloc) are indicated for treating the cardiac
arrythmias. Esmolol has very short duration of action (t1/2=9 min.) due to rapid hydrolysis of its
ester functionality by esterase present in RBC. The resultant carboxylic acid is an extremely

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
weak β-antagonist. The acid metabolite has elimination half-life of 3-4 hours & excreted
primarily by kidneys. Acebutolol & betaxolol have weak membrane stabilizing activity. Esmolol
is incompatible with NaHCO3. It must be diluted with an injection solution before
administration.
Acebutolol is converted into diacetolol, which is formed by hydrolytic conversion of amide
group to the amine, followed by acetylation of amines. After oral administration, plasma level of
diacetolol is higher than those of acebutolol. Diacetolol is also a selective β 1-antagonist with
partial agonistic activity. It has little membrane stabilizing activity, half-life of 8-12 hours &
excreted by kidneys.

Acebutolol

OH Deacetylation
CH3
O NH
CH3 CH3
Esterase (in RBC) NH
Esmolol O O
OH
CH3

HOOC H 3C

Metabolism of Esmolol NH2

Acetylation

CH3
O O NH
CH3
OH

H 3C

NHCOCH 3

Diacetolol
Metabolism of acebutolol

α-Adrenolytics/α-Blockers/α-Sympatholytics
The chemical classes, which are used as α-blockers are as follow:
1. Non-selective α-blockers
(a) Imidazolines: Tolazoline, Phentolamine
(b) Ergot alkaloids: Ergotamine, Ergotoxine, Dihydroergotamine, Dihydroergotoxine
(c) Miscellaneous: Chlorpromazine, Ketanserin
2. Irreversible (non-equilibrium) α-blockers
(a) β-Haloalkyiamines: Dibenamine, phenoxybenzamine

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Conceptual Medicinal Chemistry
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3. Selective α1-blockers
(a) Quinazolines: Prazosin, Terazosin, Doxazosin
(b) Aryl Sulphonamides: Tamsulosin
(c) Indole alkaoids: Corynanthine, Indoramine
4. Selective α2-blockers
(a) Indole alkaloids: Yohimbine
(b) Tetracyclic compounds: Mirtazapine
Unlike the β-blockers, which bear the clear structural similarities to the adrenergic receptor
agonists like norepinephrine, epinephrine & isoproterenol. The α-adrenergic receptor antagonists
consist of a number of the compounds to diverse chemical structure that bear little resemblance
to α-adrenergic agonists.
1. Non-Selective α-blockers
(a) Imidazolines
Tolazoline (Priscoline) & Phentolamine (Regitine) are imidazoline α-blockers. Both are
reversible blocking (competitive) agents. These are similar to imidazoline α1-agoniss like
naphazoline & xylometazoline but does not have the larger lipophilic substituents required for
agonistic activity i.e. intrinsic activity.
H 3C
H
N
N
N N

NH

HO
Tolazoline
2-benzyl-4,5-dihydro-1H-imidazole Phentolamine
3-[(4,5-dihydro-1H-imidazol-2-ylmethyl)
(4-methylphenyl)amino]phenol

Phentolamine is more effective α-antagonist, but neither drug is useful in treating hypertension.
Both phentolamine & tolazoline are potent, but rather non-specific α-blockers. Both drugs
stimulate gastrointestinal smooth muscles, an action blocked by atropine would indicate
cholinergic activity & they both stimulate gastric secretion, possibly through release of
histamine. Phentolamine is used to prevent or control hypertension episodes that occur in
patients with “pheochromocytoma”. It is also used in combination with papaverine in impotence.
(b) Ergot alkaloids: See hallucinogens, Chapter , Page

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
2. Irreversible (Non-equilibrium) α-blockers
(a) β-Haloalkylamines*
Agents in this class when given in adequate doses, produce a slowly developing, prolonged
adrenergic blockade that is overcome by norepinephrine. So these are called as irreversible α-
blockers. Dibenamine is the prototypical agent of this class, but phenoxybenzamine is used
therapectically today.

Cl
Cl N
N
CH3

Dibenamine
N,N-dibenzyl-2-chloroethanamine
Phenoxybenzamine
N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine

Mechnism of action of β -Haloalkylamine


β -Haloalkylamines cause the irreversible blockade of α -receptors by alkylation. β -
Haloalkylaminesare present in mustard anticancer agents & are highly active alkylating agents.
The initial step involves the formation of an intermediate aziridinium ion (ethylene iminium ion),
which forms an initial reversible complex with receptors. The unshared electrons of the
unprotonated functional group is nucleophilic & displaces the β -chlorine atom in an
intramolecular reaction to form highlt reactive, positive charged & electrophilic aziridinium ion.
If this occurs in vicinity of an α -receptor, a nucleophilic group (Nu) on the receptor can open
the aziridinium ion in a nucleophilic reaction to form a covalent bond between the receptor & the
drug. The substituents attached to haloalkylamine provide selectivity for binding to α -

These are similar to the alkylating agents like the anticancer dug “Cyclophosphamide”.
H3C O NH

N P
O
H3C

Cyclophosphamide

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
adrenoceptors, so that the nucleophile is a part of target receptor. The nucleophile (Nu) is
presumably a part of an amino acid side chain, such as cysteine thiol, serine hydroxyl or lysine
amino group. This covalent bond formed is irreversible so long lasting.
Unfortunately, other biomolecules besides the target α -receptor are also alkylated. Because of
its receptor non-selectivity & toxicity, the use of phenoxybenzamine is only limited to alleviating
the sympathetic effects of “ pheochromocytoma”. (it is tumor of chromaffin cells of adrenal
medulla producing larger amount of norepinephrine & epinephrine).

R .. Cl R
+
R Cl- R
N N Cl- +
N ..
R' R' R' N
Aziridinium ion Nu ' Nu
R

Receptor drug complex Alkylated Receptor

Phenoxybenzamine (Dibenzyline): Iit is described as representing chemical sympathectomy


because of its selective blockade of excitatory responses of smooth myocardial muscles. It causes
vasodilatation. It may also block 5-HT receptors. Blockade of Presynaptic α 2-receptors may
lead to increased heart rate. The onset of action is slow. Oral phenoxybenzamine is used for pre-
operative management of the patients with “Pheochromocytoma” & in the chronic management
of the patients whose tumors are not amenable to surgery. Only about 20-30% of an oral dose is
absorbed.
3. Selective α1-blockers
(a) Quinazoline Derivatives
Examples are Prazosin (Minipress), terazosin (Hytrin) & doxazosin (Cardura). Structurally, these
agents consist of three components i. e. quionazoline ring, piperazine ring & acyl moiety.
O

R
N
1 Drug R
8
H3CO 7 N N
2 Prazosin
6 N O
3
H3CO 5 4
NH2 Terazosin
O
O
Quinazoline ring Piperazine Acyl
Doxazosin
ring moiety O

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Structure-Activity-Relationships
1. 4- Amino moiety on the quinazoline ring is essential for α 1-receptor affinity.
2. Piperazine can be replaced with other heterocyclic moieties (e.g. piperidine) without loss
of activity.
3. The nature of acyl grouphas a significant role in determining pharmacokinetic properties
e.g. when the furan ring (Prazosin) is reduced to tetrahydrofuran ring (Terazosin) , the
compound becomes more hydrophilic, since tetrahydrofuran is more hydrophilic than
furan. In doxazosin, there is a bulky substittion (R) that causes the hindrance in
metabolism causing longer duration of action. (Table 1.6)
Prazosin, Terazosin & Doxazosin: Due to vasodilating action, these agents are used in the
treatment of hyperatension. Prazosin blocks postjunctional α 1-receptors without affecting
presynaptic α 2-receptors. These agents are also used in the treatment of BPH, where they
improve the flow-rate.
Table 1.6: Pharmacokinetic Profile of α 1-adrenergic receptor antagonists
Drug Trade Name Half-Life Duration of Bioavailability (%)
(hr) action (hr)
Prazosin Minipress 2-3 4-6 45-65
Terazosin Hytrin 12 >18 90
Doxazosin Cardura 22 18-36 65
Indoramin Doralese 5 >6 30
Tamsulosin Flomax 14-15 >24 <50% with food,
50-90% fasted

(b) Aryl sulphonamide


Tamsulosin (Flomax) is the representative of this class. It is selective for α 1A -adrenergic
receptors, predominantly in prostrate. This is indicated in treatment of BPH (by relaxing trigone
muscles of urinary bladder).
(c) Indoles
Examples of this class are indoramine (Doralese) & corynanthine.
Indoramine (Doralese) : It is an indole derivative, having a piperidine ring in the side chain. It
also blocks H1-receptors & 5-HT receptors in addition to α 1-receptors. It has antihypertensive
action.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
NH O

O
N
NH
S
O
H 3C
O O CH3 N
CH3 H

Tamsulosin Indoramin

4. Selective α2-blockers
(a) Indole alkaloids
Yohimbine & corynanthine are obtained from Pausinysilla yohimbe bark & Rauwolfia roots.
Isomeric indole alkaloids known as yohimbines exhibit different degrees of selectivity, towards
α1 & α2-adrenergic receptors, depending upon their stereochemistry. For example, yohimbine is a
selective antagonist for α2-adrenergic receptors, while corynanthine is selective α2-adrenergic
antagonist. The only difference between these two drugs is the relative stereochemistry of carbon
containing the carbomethyl substituent (C16).

9 6
9 6 8 7
8 7 10 5
10 5
H
H 11 N CH3
11 N 13 N 2 4 21
13 2 4 21 3 N
N 3 12
12 H H 20 H
H H 20 H 1
1 14 19
14 19 15 N
15
16
16 18
18 17
H 3CO 2C 17
H 3CO 2C
OH
OH

Yohimbine Corynanthine Mirtazapine


(α2-blocker) (α1-blocker)

In yohimbine, this group lies in plane of alkaloid ring system, while in corynanthine, it lies in
axial position & thus is out of the plane of the ring system. Yohimbine increases HR & BP as a
result of α 2-receptor blockade in CNS. It has been used experimentally to treat male erectile
impotence.
(b) Tetracyclic compounds
Mirtazapine (Rameron) is used toas antidepressant. It also blocks 5-HT2 & 5-HT3 receptors & H1-
receptors.
β -Blockers with α 1-receptor activity

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Two examples of such compounds are labetalol & carvediol.
(a) Labetalol (Normodyne): It is a phenylethylene derivatives & competitive inhibitor of both
β 1 &β 2 adrenoceptors. Since, it has two asymmetric carbon atoms (1 &1 ’), so it exists in four
isomers. It is used in mixture that is used in the treatment of hypertension. The α 1-blocking
solely resides in (1S,1’R) & (1S, 1’S)isomers, previous is more potent. While, β-blocking activity
resides in (1R,1’R) isomer. Labetalol is well absorbed, it exhibits first pass metabolism.
OH OCH 3

O
NH
O NH

CH3 OH
HO

CONH 2
N
H

Labetalol Carvediol

(b) Carvediol (Coreg): Only (S)- enantiomer possesses the β-blocking activity, while both
enantiomer are antagonists of α1-receptor. This drug is also an anti-oxidant & has proliferative
effect on the vascular smooth muscle cells. Thus, it has neuroprotective effect & the ability to
provide major CNS organ protection. It is used in treatment of hypertension & CHF.

Drugs inhibiting metabolism of Catecholamines


Inhibition of enzymes involved in the metabolism of norepinephrine would increase its
concentration at receptors. MAO inhibitors (MAOIs) are useful drugs comes under this category
(see Chapter Antidepressants). MAO oxidizes catecholamines by oxidative-deamination.
Oxidation proceeds through the removal of two amino hydrogens to produce an imine by enzyme
utilizing pyridoxal phosphate (vit. B6) & then by non-enzymatic hydrolysis of the resulting imine
to the aldehyde.
OH OH OH
NH2
HO HO NH H2O O
MAO HO

HO -2H
HO
HO

MAOIs can also be used as antihypertensives. This action is not compatible with their
presumable action i.e. increase in the concentration of norepinephrine at Adrenergic receptors.

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
This action has been related to alteration in the biosynthesis of norepinephrine caused by
accumulation of intermediates in the biosynthetic pathway & their metabolism of the false
neurotransmitters, which on liberation fail to activate the receptor. Octapamine is an example of
such false neurotransmitter.
CH3

NH2

HO
Octapamine

Negative feed-back due to accumulation of norepinephrine at the synaptic cleft. As tyrosine


accumulates, it is decarboxylated & hydroxylated to give octapamine.

Synthesis of Adrenergic & Antiadrenergic drugs


Guanethinidine

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
NH

NH ClCH2CN N Pt, H2 N
NH2
H2N
+NH CI N
NH NH2
CN 2

NH

GUANETHIDINE

Guanedrel
H 2N

NH
O HN
O O H2N NH
O Cl N
OH NH
HO Cl O O O H 3CS O
O
NH2NH2 NH2

O O O O

GUANEDREL

β-Phenylethylamine Derivatives
O O CH 3
HO O CH 2 Cl
ClCOCH 2 Cl Fries HO HO NH
CH 2 Cl H2NCH(CH 3 )2 CH 3
O
HO OH Rearrangement
HO (-HCl) HO
Catechol Pd, H 2
H2NC(CH 3)3
NH
2

CH 3 l) (-HCl) OH CH 3
C
O (-H HO NH
CH 3
HO CH 3
CH 2 NHCH O
3 HO
HO NH CH 3
HO
CH3
ISOPRENALINE
HO
H

2ClCOC(CH 3 )3
2

Pd
,
Pd

CH 3
,
OH
H2
CH3

OH (-2HCl) HO NH CH3
HO O H 3C 2 CH 3
CH 2 NHCH 3 (H 3 C) 3 COCO C COCl HO
CH 2 NHCH 3
HO O
CH 3
COLTEROL
ADRENALINE (H 3 C) 3 COCO O

O NH CH 3
CH 3

Pd,H 2 O

O Pd,H 2
OH
H 3C
(H 3 C) 3 COCO
CH 2 NHCH 3 H 3C

(H 3 C) 3 COCO

DIPIVEFRIN O
CH 3
O
O NH CH 3
CH 3

O
BITOLTEROL

H 3C

Terbutaline (Bricanyl, Brethine)

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
O O O CH2Ph O
PhH2CO PhH 2CO CH 2Ph PhH2CO N
Br HO NHC(CH3)3
CH3 HN
Br 2 C(CH 3) 3 C(CH3)3
Pd, C

OCH2Ph OCH 2Ph OCH2Ph


H2
OH
3,5-Bibenzyloxy
acetophenone TERBUTALINE

Salbutamol (Calbuterol, Ventonolin, Provengtil)


O O O O O CMe 3

Cl N
H 3CO H 3CO (CH3)3NHCH2Ph H 3CO
+ ClCOCH2Cl
HO HO HO
LiAlH4

OH CMe 3 O CMe 3
O CMe 3
N N
NH
Pd, C HO NaBH4 HO
HO

HO HO
HO

SALBUTAMOL

Metaraminol
O
O OH
O N OH OH
NH2 NH2
Et Et Butylnitrile
CH 3
1. Raney Ni, H2 (+) Tartaric
ClCH2Ph CH3 acid CH3
2. Pd, C, H2
OH
O O OH
O
3-Hydroxypro METARAMINOL
piohenone

Ritodrine (Yutopar)
OAc OAc OAc OAc NH2 OH
1. HO (CH 2 ) 2
ClCOCH2Cl Isoamyl H2O
nitrite H+ 2. Pt, H2
CH3 CH3 CH 3 CH3
O O O HO

N O HN
OH

OH
RITODRINE

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Methoxamine (Vasoxyl)
OH
O O N O CH3 OH CH3
H3CO H3CO
+ H3CO
1. H3O Pd, C H3CO
Et Butylnitrite NH2
CH3 NH2

OCH3 OCH3 2. NH3 OCH3


H2
OCH3

METHOXAMINE

Ephedrine
O
O
O O OH
ClCOCH2CH3 CH3 +
Et Isoamylnitrite CH3 CH3 NHCH 3
H3O CH3NH2 Pt,H2
AlCl3 N O
N
HO CH 3
H3C
EPHEDRINE

Phenylephrine
OH OH

PhH 2CO CHO COOEt COONHNH 2


PhH 2CO PhH 2 CO
BrCH2COOEt NH2NH2

Reformatsky Reaction

HNO2
H OH
OH N
O N O
NHCH 3 PhH 2CO PhH 2CO
HO 1. NaH/CH3I O

2. HCl

PHENYLEPHRINE 1

Naphazoline
H2N

EtOH H2N

HCl N
OEt
CN
N
NH H

NAPHAZOLINE

Oxymetazoline
H2N
CH 3
CH3 CH3

Isobutylchloride H2N Me 3 C
CH 2 CN Me 3 C CH 2 CN N
AlCl3
HO CH3 N
HO CH3 HO CH3
H

OXYMETAZOLINE

Cloniodine

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Cl

Cl
NH2 H H NH2
N CH3I N N
+ CS2 S S
Cl
NH
N N CH3 N
NH2 H H
Cl
CLONIDINE

Guanebenz
NH
Cl Cl
NH
H 2N NHNH 2
NH2
CHO
Hydrazinylguanidine N NH
Cl Cl

2,6-Dichloro GUANABENZ
benzyldehyde

Guanefacine
NH
Cl Cl Cl

CH3OH H2N NH 2
CH 2 COOH CH 2COOCH 3 NH NH 2
H2SO4
Cl Cl Cl O NH

GUANAFACINE

Dobutamine
(CH 2) 2COCH 3
H 3 CO NH 2 H 3CO (CH 2) 2 N H 3CO NH
p-TsOH Pd, H2
+
H 3CO Benzene H 3CO CH3
H 3 CO CH 3
2-(3,4-dimethoxyphenyl) CH 3
ethanamine 4-(4-methylphenyl)
OCH 3 OCH 3
butan-2-one
H2O/H+

HO NH

HO CH3

OH

DOBUTAMINE

Propranolol

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
CH(CH 3 ) 2
OH O NH
O
O OH
O H2NCH(CH3)2
aq. alkali
+ Cl
(- HCl)

PROPRANOLOL

Timolol
O
Cl OH Cl O Cl O
Cl HN O
Cl H2NCMe3 NHCMe 3 O
O N NHCMe 3
OH OH OH
N N N N N N N N
S S S S

TIMOLOL

Nadolol
OH OH OH O Cl O NHCMe 3
HO HO OH HO OH
O
Na AgOCOCH3 Cl H2NCMe3

Liq. NH3
I2 HO
HO HO

NADOLOL

Pindolol
CH 3

NH
OH O Cl O
O CH3
Cl OH CH3
Me2CHNH2

N N N
H H
H PINDOLOL

Acebutolol (N-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}butanamide)
CH3

OH OCOCH 3 OH O NH
O
COCH 3 1. Cl OH CH3
CH3COCl AlCl3

Fries Rearrangement 2. (CH3)2CHNH2


NHCO(CH 2 ) 2 CH 3 NHCO(CH 2) 2CH 3 NHCO(CH 2) 2CH 3 NHCO(CH 2 ) 2 CH 3

N-(4-hydroxyphenyl) ACEBUTOLOL
butanamide

Atenolol
CH3

OH OH Cl O O NH
OH
O
OH CH3
Cl (CH3)2CHNH2 OH
NaCN/NaOH H2O

DMF

H 2N COOH CONH 2 CONH 2 CONH 2


CN

ATENOLOL

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Betaxolol
CH3 CH3

OH O Cl O NH O NH
O CH3 CH3
Cl OH OH Br OH
(CH3)2CHNH2

(CH 2 ) 2 OH (CH 2 ) 2 OH (CH 2 ) 2 OH O

4-(2-hydroxy
ethyl)phenol BETAXOLOL

Esmolol (Methyl 3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}propanoate)


CH3

OH OH O NH
O CH3
OH
1. Cl

2. (CH3)2CHNH2

(CH 2 ) 2 COOH (CH 2 ) 2 COOCH 3 (CH 2 ) 2 COOCH 3

ESMOLOL

Metoprolol
(CH 2 ) 2 OMe (CH 2 ) 2 OMe (CH 2 ) 2 OMe
O
Cl Me2CHNH2

OH OH CH3

OH Cl O NH
O
CH3
4-(2-methoxyethyl)
phenol METOPROLOL

Tolazoline
NH2

OEt N
NH2
NC EtOH, HCl
NH
NH

Phenylacetonitrile TOLAZOLINE

Phentolamine
H H3C
H3C N
CH2 Cl
N N N
NH
N
H

OH
OH
3-[(4-methylphenyl) PHENTOLAMINE
amino]phenol

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Conceptual Medicinal Chemistry
Adrenergic & Anti-Adrenergic Drugs
Phenoxybenzamine
Prazosin, Terazosin, Doxazosin
Tamsulosin
Mirtazapine
Labetalol
CH3 CH3 CH3 CH3
CH3 CH3

Raney Ni Pd/C
NH2 PhCH
2CH2COCH3 N NH NH2

H2
1. PhCHO
CH3 CH3
2. Pd/C
N N BrH 2COC CONH 2
CH3
HO HO 1.
Pd/H2 OCH 2Ph
NH

2. Pt/H2

CONH 2 CONH 2

OH OCH 2 Ph

LABETALOL

Carvediol

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