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SAR OF
LOCAL ANESTHETICS
Somnath Mondal
ChemistryAll local anesthetics are weak bases, classified as tertiary amines.
IIIIIII
O
NH C CH2 N
CH2
CH2
CH3
CH3
CH3
CH3
I
I
I
I
I
I
I
I
I
IIIIII
I. AROMATIC RING
II. ESTER OR
AMIDE LINKAGE
III. HYDROCARBONCHAIN
IV. TERTIARY AMINE GROUP
Component structure of local anesthetics that form four distinct chemical subunits.
Somnath Mondal
O
C CH2 N
CH2
CH2
CH3
CH3
CH3
CH3
CH2H2N
Amino-esters
O
NH C CH2 N
CH2
CH2
CH3
CH3
CH3
CH3
Amino-amides
Somnath Mondal
O
HN C CH2 N
CH2
CH2
CH3
CH3
CH3
CH3
Procaine oORr Novocaine
Aromatic Amides
O CH2 N
CH2
CH2
CH3
CH3
O
C CH2H2N Lidocaine or lognocaine
Aromatic acid esters
C
O
O
N CH3
COO CH3
Cocaine
Natural Ester
I. AROMATIC RING
Lipophilic Portion
II. INTERMEDIATE CHAIN
Ester or amide linkage along with hydrocarbon chain
III. TERTIARY AMINE GROUP
Hydrophilic PortionSomnath Mondal
CH2 N
R2
R3I. AROMATIC RING
II. ESTER OR
AMIDE LINKAGE
III. HYDROCARBONCHAIN
IV. TERTIARY AMINE GROUP
Somnath Mondal
I.AROMATIC RING Lipophilic Portion
R1
YZ N
R3
R2
n
亲脂部分
NH S
O> > >
When par a or or t ho posi t i on have el et r on donat i ng gr uop, act i vi t y i ncr eased
The lipophilic center is usually either a carbocyclic or heterocyclic ring system
Most of the cases it is Carbocyclic and in few cases it is heterocyclic ring and their reactivity shown below
CarbocyclicAromatic ring
SN O
i) The aryl radical (Aromatic ring )attached directly to the carbonyl group enhances local anaesthetic activity. It is lipophilic centre of compound.
a) Ring Nature:
II. ESTER OR
AMIDE LINKAGE CH2 N
R2
R3III. HYDROCARBON
CHAIN
IV. TERTIARY AMINE GROUP
I. AROMATIC RING
R1
R’1
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:
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 methylene groups is substituted to aryl moiety; the maximum activity is achieved for the C4 to C6 homologues.
II. ESTER OR
AMIDE LINKAGE CH2 N
R2
R3III. HYDROCARBON
CHAIN
IV. TERTIARY AMINE GROUPR1
R’1
I. AROMATIC RING
Somnath Mondal
II. INTERMEDIATE CHAINEster or amide linkage along with hydrocarbon chain
i) Ester or amide linkage
II. ESTER OR
AMIDE LINKAGE CH2 N
R2
R3
III. HYDROCARBONCHAIN
IV. TERTIARY AMINE GROUPR1
R’1
O COOH2N CH2 CH2 N
C2H5
C2H5Procaine
C O C
O
Eg. Cocaine, Procaine, TetracaineEster
CN C
O
Amide, Lidocaine,Mepivicaine,Bupivacaine
O NH
CH3
CH3
CH2C
O
N
C2H5
C2H5LidocaineSomnath Mondal
Ester or amide linkage between the aromatic moiety and hydrocarbon chain and its modification with functional group like
C S
O
C O
O
C S
O
C N
H
O
C CH2
O
C N
H
O
C C
H2
O
affect both Pharmacodyanamics & Pharmacokinetics property of the Localanesthetics.
PharmacodyanamicsThe order of conduction anaesthetic potency i.e activity
Somnath Mondal
Pharmacokinetics properties like stability, Metabolism (metabolic product) which in turn alter the toxicity profile of the particular group of compound.
The order of Stability
C O
O
C S
O
C N
H
O
C CH2
O
Ester linkage Local anesthetics are hydrolyzed in plasma by pseudocholinesterase. One of the by-products of metabolism is paraaminobenzoicacid, 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 amide’s biotransformation depends on
Hepatic metabolic enzymes due to which amide’s derivatives are having
Longer duration of action than esters.
True allergic reactions are rare (especially with lidocaine).
Somnath Mondal
ii) Hydrocarbon chain
II. ESTER OR
AMIDE LINKAGE CH2 N
R2
R3
III. HYDROCARBONCHAIN
IV. TERTIARY AMINE GROUPR1
R’1
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
.
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.
II. ESTER OR
AMIDE LINKAGE CH2 N
R2
R3
III. HYDROCARBONCHAIN
IV. TERTIARY AMINE GROUPR1
R’1
Somnath Mondal
IIIIIII
CH2 N
R2
R3I. AROMATIC RING
II. ESTER OR
AMIDE LINKAGE
III. HYDROCARBONCHAIN
IV. TERTIARY AMINE GROUP
Somnath Mondal
IIIIIII
O
NH C CH2 N
CH2
CH2
CH3
CH3
CH3
CH3
I. AROMATIC RING
II ESTER OR
AMIDE LINKAGE
III. HYDROCARB
ONCHAIN IV. TERTIARY AMINE
GROUP
Somnath Mondal