Conformationally Restricted σ₁ Receptor Antagonists from (-)-Isopulegol

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Sigma-1 receptor antagonists are promising for neuropathic pain.
• Monoterpene (-)-isopulegol serves as a starting material for novel ligand synthesis.

Purpose of the Study:

• To synthesize and evaluate novel sigma-1 receptor ligands for neuropathic pain treatment.
• To investigate structure-activity relationships of synthesized compounds.

Main Methods:

• Chemical synthesis of aminodiols, bicyclic, and tricyclic ligands.
• In vitro sigma-1 receptor binding assays.
• In vivo antiallodynic activity assessment using capsaicin assay.
• Molecular dynamics simulations for affinity analysis.

Main Results:

• Aminodiols (8-11) displayed higher sigma-1 affinity than bicyclic (13-16) and tricyclic (19-22) derivatives.
• (R)-configured aminodiols showed greater sigma-1 affinity than (S)-configured ones.
• Compound 8b demonstrated high sigma-1 affinity (Ki = 1.2 nM), excellent selectivity, and favorable pharmacokinetic properties.
• 8b exhibited significant antiallodynic activity, reversible by a sigma-1 agonist, confirming its mechanism of action.

Conclusions:

• Aminodiol derivatives, particularly 8b, are potent and selective sigma-1 receptor antagonists.
• The synthesized compounds hold therapeutic potential for neuropathic pain management.
• Stereochemistry and structural modifications significantly impact sigma-1 receptor affinity.