SAR OF LOCAL ANESTHETICS

Somnath Mondal

All local anesthetics are weak bases, classified as tertiary amines.

I I O I I NH C I I II. ESTER I OR
I I I I I I I I I

Chemistry

CH3

CH2
III. HYDROCARBON CHAIN

CH3

AMIDE LINKAGE

I I I I I I

CH2

CH3

N CH2 CH3

I. AROMATIC RING

IV. TERTIARY AMINE GROUP

Component structure of local anesthetics that form four distinct chemical subunits.
Somnath Mondal

Amino-esters
CH3

O H2N

CH2 CH2 CH2

N

CH3

CH2
CH3

CH3

Amino-amides
CH3

O NH

CH2 CH2
N

CH3

CH2
CH3 Somnath Mondal

CH3

CH3

Aromatic Amides
H N O

CH2 CH2 N

CH3

Procaine oORr Novocaine

CH2 CH3

CH3

Aromatic acid esters

O H2 N C
O CH2 CH3

CH2

CH2

Lidocaine or lognocaine
CH2 CH3

N
Natural Ester
O C O

CH3

Cocaine
COO CH3
III. TERTIARY AMINE GROUP

II. INTERMEDIATE CHAIN

I.

AROMATIC RING

Lipophilic Portion

Ester or amide linkage along Somnath Mondal with hydrocarbon chain

Hydrophilic Portion

R2
II. ESTER OR AMIDE LINKAGE

CH2
III. HYDROCARBON CHAIN

N
IV. TERTIARY AMINE GROUP

I. AROMATIC RING

R3

Somnath Mondal

I.AROMATIC RING
a) Ring Nature:

Lipophilic Portion

i) The aryl radical (Aromatic ring )attached directly to the carbonyl group enhances local anaesthetic activity. It is lipophilic centre of compound.

R1
R2 R1
I. AROMATIC RING
II. ESTER OR AMIDE LINKAGE

CH2
III. HYDROCARBON CHAIN

IV. TERTIARY AMINE GROUP

R3

Most of the cases it is Carbocyclic and in few cases it is heterocyclic ring and their reactivity shown below

Carbocyclic Aromatic ring

N
Somnath Mondal

ii) The compounds containing aryl-vinyl group (Ar-CH = CH -) does not having local anaesthetic activity, because of the mesomeric effect of aryl radical does not extend to carbonyl group.

iii) Alicyclic and aryl aliphatic carboxylic acid esters are also active local anesthetics

Somnath Mondal

b) Aromatic ring Substituents:

R1 R2 R1
I. AROMATIC RING
II. ESTER OR AMIDE LINKAGE

CH2
III. HYDROCARBON CHAIN

IV. TERTIARY AMINE GROUP

R3

Local anaesthetic activity improves if the aryl lipophilic center (Specially ortho or Para) has electron donor substitution but decreases with electron acceptor substituents. This is may be due to i) Electron releasing group alkoxy, amino and alkyl amino by releasing electron .. increases electron density of carbonyl oxygen.impart more stability to this group ..hence enhances the activity.

ii) Some believe that the electron releasing group (e.g. alkyl substitution CH3) in aryl group at ortho or Para position enhances the activity by providing steric hindrance to the hydrolysis of amide linkage and contributes lipid solubility. iii) The number of methyleneSomnath Mondal substituted to aryl moiety; the groups is maximum activity is achieved for the C4 to C6 homologues.

II. INTERMEDIATE CHAIN Ester or amide linkage along with hydrocarbon chain
O
R1 C

C
R2 CH2 N
IV. TERTIARY AMINE GROUP

R1

II. ESTER OR AMIDE LINKAGE

III. HYDROCARBON CHAIN

O
i) Ester or amide linkage

R3

Ester
Amide,

Eg. Cocaine, Procaine, Tetracaine Lidocaine,Mepivicaine,Bupivacaine

H2N

O
O

COO

CH2
Procaine

CH2

C2H5 C2H5

CH3

C2H5 CH2 N
C2 H 5

NH

Lidocaine Somnath Mondal

CH3

Ester or amide linkage between the aromatic moiety and hydrocarbon chain and its modification with functional group like
O
C S

O
C N H

O
C

C H2

affect both Pharmacodyanamics & Pharmacokinetics property of the Local anesthetics. Pharmacodyanamics
The order of conduction anaesthetic potency i.e activity
O C S O O C CH2 O

N H

Somnath Mondal

Pharmacokinetics properties like stability, Metabolism (metabolic product)

The order of Stability
O C CH2 O
C N H O

which in turn alter the toxicity profile of the particular group of compound.

O S
C O

Ester linkage Local anesthetics are hydrolyzed in plasma by pseudo cholinesterase. One of the by-products of metabolism is paraaminobenzoic acid, the common cause of allergic reactions seen with these agents.

Where, as amide linkage Local anesthetics, are having very low incidence of allergic reaction as amides biotransformation depends on Hepatic metabolic enzymes due to which amides derivatives are having Longer duration of action than esters. True allergic reactions are rare (especially with lidocaine).
Somnath Mondal

ii) Hydrocarbon chain

R1
R2
II. ESTER OR AMIDE LINKAGE

R1

III. HYDROCARBON CHAIN

CH2

IV. TERTIARY AMINE GROUP

R3

2-3 carbon short chain is optimum for local anesthetics activity, chain length more than 3 carbon atom decreases the activity.

Somnath Mondal

III.HYDROPHILIC PORTION
R1 R2 R1
.
II. ESTER OR AMIDE LINKAGE

III. HYDROCARBON CHAIN

CH2

IV. TERTIARY AMINE GROUP

R3

The amino alkyl group is the hydrophilic part of molecule. In general amino alkyl group is not necessary for activity, but it is used to from water soluble salts. . Example : Benzocaine

Hence, depending, upon the nature of the nitrogen of the amino group, both activity of local anaesthetic and irritation property alters. Hence, Most of the available compounds are having tertiary nitrogen atom. For optimum activity, the Nitrogen must be Tertiary (3o) or Secondary (2o). But when the nitrogen atom is Primary (1o) both the activity and irritant properties changes i.e activity decreases and irritant property increases.
Somnath Mondal

I. AROMATIC RING

I I I I I I I

R2
II. ESTER OR AMIDE LINKAGE

CH2
III. HYDROCARBON CHAIN

N
IV. TERTIARY AMINE GROUP

R3

Somnath Mondal

CH
3

I I I I I NH I I

O C CH2 III. HYDROCARB ON CHAIN N

CH2

CH3

CH
3

II ESTER OR AMIDE LINKAGE

CH2

CH3

I. AROMATIC RING

IV. TERTIARY AMINE GROUP

Somnath Mondal