Structure Activity Relationships of Local Anesthetics

1. Structure Activity Relationshipsof Local Anesthetics

2. 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

3. 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

4. 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

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

6. Structure Activity Relationships

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

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

9. Amino Esters Ester Lipophilic center 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

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

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

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

13. 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

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

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

16. Amino Amides Carbon bridge Tertiary amine Lipophilic center Amide Lidocaine (Xylocaine) The o,o-dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

17. Amino Amides Cyclic tertiary amine Lipophilic center Amide 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)

18. Amino Amides Cyclic tertiary amine Lipophilic center Amide 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)

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

20. Amino Amides Lipophilic center Cyclic tertiary amine Amide 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)

21. Amino Amides Carbon bridge Secondary amine Lipophilic center Amide 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

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

23. Amino Amides Articaine (Septocaine)

24. Amino Ether Lipophilic center Ether Carbon bridge Tertiary amine Pramoxine (Anusol, Tronothane, Proxine, Tronolane, Pramocaine) Lipophilic group has an alkoxy substituent Nitrogen is in a morpholino ring

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