From α4β2 Nicotinic Ligands to the Discovery of σ1 Receptor Ligands: Pharmacophore Analysis and Rational Design

Abstract

Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (<b>15</b>). Compound <b>15</b> displayed high selectivity for the σ1 receptor (<i>K</i>_i, σ1 = 4.1 nM, <i>K</i>_i, σ2 = 1312 nM) with moderate binding affinity for the DAT (<i>K</i>_i = 373 nM) and NET (<i>K</i>_i = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modifica tion could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors.