Structure Activity Relationships of Local Anesthetics.

Structure Activity Relationshipsof Local Anesthetics

Lipophiliccenter

Ester or amidegroup

Bridge Hydrophyliccenter

carbocyclic or heterocylic (Important for diffusion acrossmembrane).

Secondary or tertiary amine, cyclic or non-cylic.

Short C-chain,O, N or S.

Structure Activity Relationships

Lipophiliccenter

Ester or amidegroup





Lipophilic Portion is essential for local anesthetic activityEither an aromatic group directly attached to a carbonyl function (amino esters) or a 2,6-dimethylphenyl group attached to a carbonyl function through an –NH- group (amino amides)

These groups plan an important role in the binding of local anesthetics to the channelreceptor proteins


Lipophiliccenter

Ester or amidegroup





Intermediate ChainThe intermediate chain includes the ester or amide group and the bridgeThis chain almost always contains a chort chain of one to three carbons in length linked to the aromatic ring (lipophilic center)Amino amides are more resistant to metabolic inactivation than the amino estersand are thus longer actingSmall alkyl groups around the ester function or the amide function hinders esteraseor amidase catalyzed hydrolysis prolonging the duration of action


Lipophiliccenter

Ester or amidegroup





Hydrophilic PortionMost clinically useful local anesthetics have a tertiary alkylamine which readilyforms water soluble salts suitable for pharmaceutical preparations

The hydrophilic group can be in the form of a secondary or tertiary amine orpart of a nitrogen heterocycle

Short C-chainO, N or S

General Structure of Local Anesthetics


C O

O

CH2CH2 NH

CH2CH3

CH2CH3

R

Receptor

Van der Waal'sForces

Dipole-DipoleAttraction



Cl

Electrostatic Forces

C O

O

RO

C O

O

O2N

E-Donators increase polorization of C=O E-Acceptors decrease polorization of C=O

Amino Esters

Lipophilic center Ester Carbonbridge

Tertiary amine

An electron donating substituent in the ortho or para or both positions of thelipophilic center increases potency

O

O

N (C2H5)2

R

R1

Amino Esters

Lipophilic center

EsterCarbonbridge Tertiary amine

Cocaine

No substitutions on the lipophilic center

Amino Esters

Lipophilic center EsterCarbonchain

No terminal amine

Benzocaine (Americaine)

In para position of the lipophilic center there is an amino groupLacks the basic aliphatic amine function yet has potent local anesthetic activityUsed topically

H2N

O

O

Amino Esters

Lipophilic centerEster

Carbonchain

Tertiary amine

Tetracaine (pontocaine, Amethocaine, Prax)

In para position of the lipophilic center there is an alkylamino group

C4H9NH

O

O

N(CH3)2

Amino Esters


Tertiary amine

O

O

N (C2H5)2

H

H2N

Procaine (Novocain)

In the ortho position there is a hydrogen and in the para position there is an amino

Amino Esters

Lipophilic center EsterCarbonbridge

Tertiary amine

Chloroprocaine (Nesacaine)

In the ortho position there is a chloro and in the para position there is an amino

O

O

N (C2H5)2

Cl

H2N


• An electron-donating substituent in the ortho or para or both positions increases local anesthetic potency

• Groups such as:– an amino (procaine and chloroprocaine)– An alkylamino (tetracaine)– Contribute electron density to the aromatic

ring by both resonance and inductive effects, thereby enhancing local anesthetic potency over nonsubstituted analog

Amino Esters


Tertiary amine

When an amino or an alkoxy group is attached to the meta position of the aromatic ringthere is no resonance delocalization of electrons.

O

O

N (C2H5)2

R1

R

Amino Esters

Proparacaine (Alcaine, Ophthaine, AK-Taine)

There is an amino group in the meta positionThis group will decrease lipophilicity of the molecule

Lipophilic center EsterCarbonbridge

Tertiary amine

H2N

C3H7O

O

O

N (C2H5)2

Amino Amides

Lidocaine (Xylocaine)

The o,o-dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

Lipophilic center Amide

Carbonbridge

Tertiary amine

N

C N(C2H5)2

H

O

Amino Amides

Mepivacaine (Carbocaine, Polocaine, Isocaine)The o,o-dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

No carbon bridge

Cyclic amine (piperidine)

Lipophilic center AmideCyclic tertiary amine

N

C N

H

O

Amino Amides

Bupivacaine (Marcaine, Sensorcaine)The o,o-dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

No carbon bridge



N

C N

H

O C4H9

Amino Amides

Levobupivacaine (Chirocaine)


Amino Amides

Ropivacaine [S (-) isomer]The o,o-dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

No carbon bridge


Lipophilic center

Amide

Cyclic tertiary amine

Amino Amides

Prilocaine (Citanest)The o,o-dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

Secondary amine

Lipophilic center AmideSecondary amine

N

C NH

H

O C3H7Carbonbridge

Amino Amides

Dibucaine (Nupercainal, Cinchocaine)

The lipophilic group is the bicyclic quinoline

Tertiary amine

Lipophilic center AmideTertiary amine

Carbonbridge

N

C4H9O

N

N(C2H5)2

O

H

Amino Amides

Articaine (Septocaine)

Amino Ether

Pramoxine (Anusol, Tronothane, Proxine, Tronolane, Pramocaine)

Lipophilic group has an alkoxy substituent

Nitrogen is in a morpholino ring

Lipophilic center EtherTertiary amine

Carbonbridge

C4H9O

O N O

Amino Ketone

Dyclonine (Dyclocaine, Dyclone, Sucrets)

Lipophilic group has an alkoxy substituent

Nitrogen is in a piperidine ring

Lipophilic center

Ketone Tertiary aminePiperidine

Carbonbridge

C4H9O

C

O

N

Structure Activity Relationships of Local Anesthetics.

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