From α4β2 nicotinic ligands to the discovery of σ1 receptor ligands: Pharmacophore analysis and rational design

Li Fang Yu, Han Kun Zhang, Hendra Gunosewoyo, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1054-1058
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume3
Issue number12
DOIs
StatePublished - Dec 13 2012

Keywords

  • Nicotinic acetylcholine receptor
  • alkoxyisoxazole
  • broad screening
  • pharmacophore
  • sigma-1 receptor

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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