Structure Activity Relationships of Local Anesthetics

Structure Activity Relationships Lipophilic Portion is essential for local anesthetic activity Either 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 channel receptor proteins

Structure Activity Relationships Intermediate Chain The intermediate chain includes the ester or amide group and the bridge This 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 esters and are thus longer acting Small alkyl groups around the ester function or the amide function hinders esterase or amidase catalyzed hydrolysis prolonging the duration of action

Structure Activity Relationships Hydrophilic Portion Most clinically useful local anesthetics have a tertiary alkylamine which readily forms water soluble salts suitable for pharmaceutical preparations The hydrophilic group can be in the form of a secondary or tertiary amine or part of a nitrogen heterocycle

Short C-chain O, N or S General Structure of Local Anesthetics

Structure Activity Relationships

Amino Esters Lipophilic center Ester Carbon bridge Tertiary amine An electron donating substituent in the ortho or para or both positions of the lipophilic center increases potency

Amino Esters Lipophilic center Ester Carbon bridge Tertiary amine Cocaine No substitutions on the lipophilic center

Amino Esters Lipophilic center Ester Carbon chain No terminal amine Benzocaine (Americaine) In para position of the lipophilic center there is an amino group Lacks the basic aliphatic amine function yet has potent local anesthetic activity Used topically

Amino Esters Lipophilic center Ester Carbon chain Tertiary amine Tetracaine (pontocaine, Amethocaine, Prax) In para position of the lipophilic center there is an alkylamino group

Amino Esters Lipophilic center EsterCarbon bridge Tertiary amine Procaine (Novocain) In the ortho position there is a hydrogen and in the para position there is an amino

Amino Esters Lipophilic centerEster Carbon bridge Tertiary amine Chloroprocaine (Nesacaine) In the ortho position there is a chloro and in the para position there is an amino

Structure Activity Relationships 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 Lipophilic center Ester Carbon bridge Tertiary amine When an amino or an alkoxy group is attached to the meta position of the aromatic ring there is no resonance delocalization of electrons.

Amino Esters Proparacaine (Alcaine, Ophthaine, AK-Taine) There is an amino group in the meta position This group will decrease lipophilicity of the molecule Lipophilic centerEster Carbon bridge Tertiary amine

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 Carbon bridge Tertiary amine

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 Amide Cyclic tertiary amine

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 Cyclic amine (piperidine) Lipophilic center Amide Cyclic tertiary amine

Amino Amides Levobupivacaine (Chirocaine) Lipophilic center Amide Cyclic tertiary amine

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 Cyclic amine (piperidine) 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 Amide Secondary amine Carbon bridge

Amino Amides Dibucaine (Nupercainal, Cinchocaine) The lipophilic group is the bicyclic quinoline Tertiary amine Lipophilic center Amide Tertiary amine Carbon bridge

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 Ether Tertiary amine Carbon bridge

Amino Ketone Dyclonine (Dyclocaine, Dyclone, Sucrets) Lipophilic group has an alkoxy substituent Nitrogen is in a piperidine ring Lipophilic center Ketone Tertiary amine Piperidine Carbon bridge