Analgesics and Anti-inflammatory drugs

613 352 Pharmaceutical Chemistry by Assist.Prof.Dr.Suthasinee T.

Objective:
To understand and explain the structure and activity relationship of each drug group

Details
1. History 2. Classification by structure 2.1 Morphine and related compounds 2.2 Anti-inflammatory analgesics 1) Salicylic acid derivatives 2) Anilline and p-Aminophenol Derivatives 3) Pyrazolone and Pyrazolidinedione Derivatives 4) Arylacetic acid Derivatives 5) N-Arylanthranillic acid (Fenamic Acids) 6) Aryalkanoic acid 7) 2-Arylpropionic acids (profen) and Oxicams 8) Coxib drugs 3. Conclusion
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History of Analgesics
1. Discovery ,use natural plant 2. Isolate compound from plant, identify analgelsic action

3. Development of organic chemistry first synthetic analgelsic

4. Devlopment of modern pharmacological technique

discovery of opioid receptors and endogenous chemicals that have analgesic activity
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Opioids
Opioids = chemicals that work by binding to opioid receptor Opioid receptor = natural located proteins to which opioid-

agents bind and initiate biologic response

Effects of opioids - decreased perception of pain, decreased

reaction to pain as well as increased pain tolerance

side effects : sedation, respiratory depression,

and constipation. Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect

Opioids sources :
Opium alkaloids Naturally occurring Synthetic derivatives related to Opium alkaloids Synthetic peptides with morphine-like

pharmacologic effects

Opioids
Endogenous opioids: Opioid-peptides -Enkephalin= pentapeptide
Exogeneous opioids: -opioid alkaloids -synthetic opioids derivatives

Opioids receptors
Tyr-Gly-Gly-Phe-Met (Met-enkephalin) Tyr-Gly-Gly-Phe-Leu (Leu-enkephalin)

--endorphin -dynorphins -endomorphine

Opioid activity

Opioid receptors
3 major subtypes of opioid receptors with selective endogenous opioids: 1. Mu() (OP3)- Endomorphin-1 (Tyr-Pro-Trp-PheNH2) 2. Kappa (k) (OP2)- Dynorphins ( A, B, alpha- and beta-neoendorphin, and big dynorphin) 3. Delta (d) (OP1)- : Enkephalins

Mechanism of Opioids
Interactions with one or more subtypes of opioid

receptors, in example mu-, delta- and kappa- causing analgesia, and many other effects. Opioid analgesics can be full agonists of opioid receptors ( (mu)-receptor), partial -agonist and mixed agonist-antagonists have opposite effects.

Terminology
Pure Agonist: has affinity for binding plus

efficacy Pure Antagonist: has affinity for binding but no efficacy; blocks action of endogenous and exogenous ligands Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an antagonist effect at another Partial Agonist: has affinity for binding but low efficacy
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Serpentine models for opioid receptors

=schematic diagram for each of the four rat

opioid receptor subtype classes showing the sequence of the 7 transmembrane domains as well as the intraand extracellular loops
Opioid mechanism model http://www.youtube.com/watch?v=YCz5A8ZkavM (4.28 min) Each opioid receptor: http://www.youtube.com/watch?v=LT80LeQNO10&feature=related (8.57 min) 7 transmembrane domain or Serpentine receptor http://www.youtube.com/watch?v=4V51oNsjq_k&feature=results_video&playne xt=1&list=PL135D6D2DC7479E87 (
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Model of the 7 transmembrane domains

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 receptor

http://www. aapsj.org/vi ew.asp?art =aapsj0801 15

Serpentine model of the receptor. Circles contain the 1-letter code for the given amino
acid. Green lines indicate the beginning and ends of the helices. The gray circles indicate the residues that are conserved among all 3 receptor types (, , and ), while the black circles indicate the residues that are highly conserved. Each transmembrane (TM) region is indicated by a roman numeral. At the beginning and end of each helix there are Arabic numbers starting with 1 and ending at 25 (variable, depending on helix length).

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Serpentine model of the receptor

http://www.o pioid.umn.ed u/pics/OPR M.gif

Proposed model for membrane topography of the rat -opioid receptor. Amino acid residues of -opioid receptor : Black = conserved in both d- and k-receptors, Gray = in either d- and k -receptors, White = in neither d- nor k-receptor Branched structures show the potential N-linked glycosylation sites. (Reprinted from Minami and Satoh,51 with permission of Elsevier Science.)
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Serpentine model of the kappa receptor

http://www.opioid.umn.edu/pics/OPRK.gif

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Receptor delta () OP1

Subtype s 1, 2

Location brain peripheral sensory neurons

Function analgesia antidepressant effects physical dependence

kappa () OP2

1, 2, 3

brain spinal cord peripheral sensory neurons

analgesia sedation miosis inhibition of ADH release dysphoria 1: analgesia physical dependence 2: respiratory depression miosis euphoria reduced GI motility physical dependence 3: unknown anxiety depression appetite development of tolerance to 15 agonists

mu () OP3

1, 2, 3

brain spinal cord peripheral sensory neurons intestinal tract

Nociceptin receptor OP4

(orphanin)

ORL1

brain spinal cord

Mu() opioid receptor (MOR)

-receptor has high affinity for enkephalins

and beta-endorphin but low affinity for dynorphins. Activation of the receptor by an agonist (as morphine) causes analgesia , sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation.

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Opioid pharmacophore
Morphine is a prototype of opioids

Morphine

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Compound selective for mu (OP3)opioid receptors (MOR)

Prototype
2-thiophenyl 2-phenylethyl

Fentanyl

10 fold selective for

5-10xfentanyl Short onset 100 fold selectivity

80xmorphine potent Short onset

Endogeneous opioid

high selectivity, in experiment with rat

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Mu() opioid agonists

tetrazole

Acetyl ester Alfentanyl

x fentanyl 4X Fast onset than fentanyl 1/3 Short duration of action than fentanyl

Remifentanyl 250 x morphine potent 10-15x alfentanyl Selective for mu opioid receptor Fast onset 1-3 min ( Ester linkage which undergoes rapid hydrolysis by non-specific tissue and plasma esterases).
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Heroin

It is the 3,6-diacetyl derivative of morphine

(diacetylmorphine) and is synthesized by acetylation. Heroin is a -opioid (mu-opioid) agonist. It acts on opioid receptors. = morphine prodrug 3X morphine potent
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Compound selective for mu (OP3)opioid receptors

Mu() opioid agonists

Tramadol
lower risk of opioid dependence

Etorphine

Dihydroetorphine

synthetic analogue of codeine 10 x morphine potent Use:postoperative pain

10,000 x morphine potent Use for large mammals (Veterinary use)

=derivative of etorphine 1000 -12,000 x morphine potent Mild S/E 21 Use for large mammals

Compound selective for mu (OP3)opioid receptors

allyl (prop-2-enyl)
methylcyclopropane

Nalorphine antagonist, k agonist

extremely high affinity for dependence Treat opiate overdose Competitive antagonist for
and k alcohol dependence and opioid

beta-funaltrexamine

reversible kappa agonist and long acting antagonist

most selective for 30 X selective for over k 100 X selctive for over d

Cyclic peptide analog of somatostatin Treat opiate addiction

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Active and inactive -opioid receptors

Methadone

synthetic opioid, used medically as an analgesic

and in the treatment for heroin (diamorphine) addiction

used in managing chronic pain due to its long

duration of action and very low cost Levomethadone is active form

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Kappa (k) opioid receptor

endogenous ligands for the Kappa receptordynorphins.
mixed (partial) agonist/antagonist analgesic

drugs e.g., butorphanol, nalbuphine, pentazocine and naloxone (Non-specific opioid receptor antagonists ) mixed opioid agonist/antagonist- buprenorphine can be used to reverse the effects of kappa agonists
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Effects of buprenorphine, heroin and naloxone on the mu opioid receptor

Buprenorphine (Subutex)

Buprenorphine is a semi-synthetic opioid that is used to treat opioid addiction. -extremely high binding affinity at the - and -opioid receptor. -can displace both naloxone and heroin, and naloxone can displace heroin. -binds more strongly to receptors in the brain than do other opioids
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Compound selective for kappa (OP2)opioid receptors

SE: diuresis, sedation, Dysphoria (hallucination)

1000 fold selective for k over or d

3-4 X morphine

50 fold selective for k over

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Compound selective for kappa (OP2)opioid receptors

Selective k

100 fold selective for k over d

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Classification of Opioids

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Delta (d) opioid receptor

endogenous ligands for the receptor are the enkephalins.
Delta-Selective Opiates- naltrindole (NTI) and 7-

spiroindanyloxymorphone (SIOM) For these -selective ligands, however, a hydrophobic group ; indole or spiroindane forms the address (NTI and SIOM, respectively).

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naltrindole (NTI) and 7spiroindanyloxymorphone (SIOM)

spiroindane indole

spiroindane

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Compound selective for delta (OP1)opioid receptors

Peptide agonist

Modify amino acid composition of enkephalin high potency and selectivity for d Cyclic peptide enkephalin

Non peptide agonist

Endogeneous Enkephalin

Newer and more selective to d

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http://en.wikipedia.org/wiki/Delta_Opioid_receptor
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Compound selective for delta (OP1)opioid receptors

Highly selective

Peptidyl antagonist

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Nonselective Opiates
Naltrexone

a universal opiate antagonist a universal opiate antagonist. It and the closely related nonselective opiates naloxone41 and diprenorphine42 all bind to the , , and receptors with very high affinity.

Morphine and related compounds (Narcotic anagelsics)

Morphine = Alkaloid from opium (Papaver somniferum) is narcotic analgelsic. Extracted by Serturner, 1803 = prototype opioid selective for mu opioid receptor Morphine and related compounds are from 3 sources 1. Alkaloid from opium ; Morphine, Codeine, Noscapine, Papaverine and Thebaine. 2. Semi-synthetic from opium alkaloids ;Heroine, Hydrocodone,
Hydromorphone, Oxycodone, Oxymorphone

3. Synthetic compounds; Fentanyl , Alfentanil , Sufentanil Remifentanil,

Ohmefentanyl
200xMor 6300xMor
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100xMor

1/10xFen

5-10xMor

2 Main structures of Natural Opiates

1.Phenanthrene : Morphine , Codeine,

Heroine CNS depressant , sedation, euphoria, physical dependence,
Side effect: Respiratory depression

3 fused benzene ring

and addiction

2. Benzylisoquinoline: Papaverine,
noscapine Low active to CNS more Antispasmodic action

Benzyl

Isoquinoline

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Compounds from Opium

Opium = latex produced within the seed pods of the opium poppy, Papaver somniferum.

codeine
antitussive, antidiarrhea low analgesic

noscapine
antitussive agent

thebaine
cause convulsion convert to various compounds

papaverine
narcotic analgesic smooth muscle relaxant
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potent opiate analgesic psychoactive drug

Morphinan structure
Morphine is one in class of Morphinan

structure Morphinan - base chemical structure of a large chemical class of some activity
psychoactive drugs; opioid analgesics, cough suppressants, hallucinogens

Morphinan

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Morphine and related compounds

Semi-synthesis Natural Natural

Hydrocodone

Semi-synthesis

Semi-synthesis

(Oxycodon) an aromatic ring and a quaternary carbon atom linked to a tertiary amine group by two other carbon atoms. a methyl group attached to a nitrogen atom
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Morphine structure
A E C B D

B
E
(5)

(9)

C
(6)

is alkaloid from opium Papaver somniferum Compose of five fused rings and five chiral centers (5(R), 6(S), 9(R), 13(S), and 14(R) target site at mu , kappa, delta, norciceptin receptor For treatment of dysentary, pain common toxicity ; respiratory depression, constipation, addiction

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Metabolism of Morphine
3
3

2 1 In liver Sulfotranferase or glucuronyltranferase

Opioid act to CNS

3-glucuronide

Normorphine (N- and O-conjugate) excretion

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Important functional groups for analgesic activity in morphine

Important functional groups of morphine binding to receptor:

1. 2. 3. Phenolic group bind with receptor via H-bond Aromatic ring bind with receptor via Van der Waal force Amino group bind with receptor via Ionic bond
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Anionic Site

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Mu opioid receptor model

1954
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Different opioids bind to different surface area on mu receptor

1960s

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Mu receptor binding site

Endogeneous opioid Exogeneous opioid
Tyrosine binding site

enkephalin morphine meperidine

Enkephalin binding site

Phenylalanine binding site

Meperidine (or pethidine) = synthetic opioid, Lower potency analgelsic, short duration, safer and carry less risk of addiction than morphine

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Morphine SAR
Structure morphine 5 fused rings , 5 chiral center with absolute configuration 5(R), 6(S), 9(R), 13(S),14(R) Naturally occurring morphine = levo (-) rotatory

phenylethyl Allyl
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Important SAR of Morphine

1. Ring A and basic nitrogen is necessary for Mu receptor agonist
2. In compound having rigid structure

(fused A, B and D); 3-OH and tertiary nitrogen increase activity

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Ideal opioids
Morphine derivatives and other mu agonists

Find new analgesics:

improve pharmacologic properties over mu

agonists strong analgesic properties low SE (: tolerance, physical dependence, respiratory depression, emesis, constipation

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SAR at N-atom
Tertiary amine good opioid activity N-substituent as CH3 good agonist size of N-substituent (3-4 C es. Unsat. Or

small carbocylic ring) antagonist Larger N-substituent to agonist N-substituent as N-phenylethyl 10 x than N-CH3 for Mu agonist

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SAR at 3-OH
Codeine 3-methoxy der. Of morphine
Weak mu agonist but can be metabolited to

morphine by O-demethylation Potent antitussive agent

Heroin 3,6-diacyl der.

Not disturb digestion Low affinity for Mu receptor High lipophilicity entrance BBB (rapid penetrate 3 6

to brain after IV dose) Metabolited by esterase to 6-acetyl morphine (mu agonist as morphine) Euphoria rush popular for drug abuse ( cause HIV, hepatitis, infection by use the same syringe)

1874- synthesis 1898 to market by Friedrich Bayer Co. Ger.

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SAR at ring C
Morphine

Hydromorphone 7,8-dihydro-6keto der. of morphine (8-10 X )

Hydrocodone 3-methoxy der. of hydromorphone (active > codeine)
3

A B C

E
6 7 8

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SAR at 14b-OH-6-keto der.

Thebaine synthetic to 14b3 Thebaine 14

hydroxy-6-ketone der. of morphine

mu agonist antitussive activity
6 3

Oxycodone - 3-methoxy-N-methyl

der.
Potent ~ morphine Oral:parenteral > morphine

Oxycodone 6
14

Oxymorpone - 3-hydroxy-N-methyl

der.
10X morphine

14 6
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SAR at 14b-OH-6-keto der.

Nalbuphine N-cyclobutylmethyl (for
For k receptor x morphine =antagonist at mu receptor

N-methyl) and red. Of 6-ketone to 6-bOH of oxymorphone

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Nalbuphine
6

Naloxone Naloxone N-allyl-

noroxymorphone
Pure opioid antagonist Slightly mu receptor selective Naloxone
6
14

Naltrexone N-cyclopropylmethyl-

noroxymorphone
Pure opioid antagonist Slightly mu receptor selective
6

Naltrexone
14

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SAR at 14b-OH-6-keto derivatives

Oripavines from rx of thebaine + dienophiles

(i.e. Diels-Alder rx) endoethenotetrahydrothebaine der.

Potent mu agonists
Etorphine (respiratory depressant

action, not use for medical practice, use for veterinary (immobilization of large animal)) = 1000X morphine Buprenorphine (marketed) = 20-30X morphine

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SAR at 3,4-epoxide Bridge

Remove of 3,4-epoxide Bridge from
Morphine

total synthesis Morphinans

Levo(-) isomer opioid activity Dextro(+) isomer antitussive

Levorphanol- affinity for mu opioid

receptor, 10Xmorphine (analgesics), greater lipophilicity Butorpharnol mu antagonist and kappa agonist

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Benzomorphane
lack epoxide ring and ring C

Morphine

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SAR of Benzomorphans
Syth. comp. lack epoxide ring and ring C retain

opioid act. = der. of 6,7-benzomorphan or 2,6metano-3-benzazocine

Pentazocine (in US market)- aginist act.on k

opioid rec. analgesia, 0.5x morphine

Weak antagonist at rec. SE- dysphoric (higher dose )

Pentazocine

Phenazocine -N-phenylethyl der. (in Europe

market)
10X morphine as agonist

Phenazocine

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SAR as 4-phenylpiperidines
Ring A,D analogs of morphine Meperidine 1937 syn. for
Meperidine

antispasmodic
For mu rec., x morphine, short

duration

prodine

a-and b-prodine 3-methyl

reversed ester der. of meperidine

removed from US market b/c low
1 5

prescription volume and eliminate to neurotoxic agent

Trimeperidine or g-promedol

1,2,5-trimethyl reserved of meperidine

Russia analgesic

Trimeperidine
5 12

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SAR of anilidopiperidine
Modification of 4-phenylpiperidine fentanyl

gr analogs (substitution of an isosteric ring for phenyl)

o Mu agonists o Typical morphine-like analgesia o Higher safety
5-10xfentanyl

2-phenylethyl

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SAR of diphenylheptanone
Methadone-oral long duration In US market as racemice ()

(-) isomer analgesic act.

Acetylmethadols red. of

keto and acetylation of resulting -OH Diphenoxylate and loperamide

Antidiarrheal opioids

Propoxyphene weak mu

agonist

1/15 x morphine Loperamide -antidiarreal

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New Opioids: Tapentadol (Nucynta )

Tapentadol

Tramadol

was developed by Grnenthal in conjunction with Johnson & Johnson Pharmaceutical Research and Development. . It is being marketed as immediate release oral tablets of 50 mg, 75 mg, and 100 mg approved in the United States in more than 25 years a centrally acting analgesic with a dual mode of action as an agonist at the -opioid receptor and as a norepinephrine reuptake inhibitor Its structur is similar to tramadol (Ultram). It has opioid and nonopioid acitivity in a single compound. similar levels of more potent narcotic analgesics such as hydrocodone, oxycodone, and meperidine

http://en.wikipedia.org/wiki/Tapentadol

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