Local Anesthetics - Med Chem

Introductory Anesthesia Definitions

Local Anesthetics: Background & History

Local Anesthetics: Therapeutic Utility

Local Anesthetics: Formulations

Characteristics of an Ideal Local Anesthetic

Structural Classes: Tropane-related

Tropane-related Alkaloids: Structural Features

Tropane-related Alkaloids: Structural Features

• Aminoalkyl Esters

Tropane-related Alkaloids: Other Aminoalkyl Esters

Tropane-related Alkaloids: Other Aminoalkyl Esters

• Aqueous stability & metabolic stability

Tropane-related Alkaloids: Other Aminoalkyl Esters

• Antigenicity

Structural Classes: Isogramine-related Alkaloids & “Reverse Amides” as bioisosteric modifications

Structural Features: Isogramine-related Alkaloids & “Reverse Amides” Aminoalkyl Amides

Isogramine-related Aminoalkyl Amides: Structural Features

Notice:

Identify the lipophilic group, ionizable amine and distance between it and the amide carbonyl group

Other Classes of Local Anesthetics

• Aminoalkyl ethers

• Aminoalkylphenylketones

Other Classes of Local Anesthetics

• Alcohols, phenols and a benzoic acid esters

Local Anesthetic Mechanism of Action

• Target: The sodium channel

Local Anesthetic Mechanism of Action

• Resonance and the formation of zwitterions

Pathways

Structure-activity relationships (SAR) and pKa

Structure-activity relationships (SAR) and distance between the ionizable amine and the lipophilic group

Structure-activity relationships (SAR) and the lipophilic group

Resonance

Structure-activity relationships (SAR) and the lipophilic group

Steric hindrance

Structure-activity relationships (SAR) and the lipophilic group

Hydrophobicity

Structure-activity relationships (SAR) and the lipophilic group

Examples

Structure-activity relationships (SAR) and configuration

Structure-activity relationships (SAR) and substitution between the amine and aromatic ring

Local Anesthetic Metabolic Transformations

Local Anesthetic Metabolic Transformations Summary