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

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journal contribution
posted on 13.12.2012, 00:00 by Li-Fang Yu, Han-Kun Zhang, Hendra Gunosewoyo, Alan P. Kozikowski
Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound 15 displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM; Ki, σ2 = 1312 nM) with moderate binding affinity for the DAT (Ki = 373 nM) and NET (Ki = 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 modification could be used as a tool to switch a ligand’s selectivity between nAChRs and sigma receptors.

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