Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular modeling of constrained epibatidine analogues

Zhi Liang Wei, Pavel A. Petukhov, Yingxian Xiao, Werner Tückmantel, Clifford George, Kenneth J. Kellar, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

Abstract

Conformationally constrained epibatidine analogues 20a,b and 23a,b were synthesized using a radical cyclization as the key step. Radioligand displacement assays to six defined rat nicotinic acetylcholine receptor (nAChR) subtypes showed that 20a,b bind with moderate affinities, while 23a,b have low affinities. 20a exhibits higher affinity for the β2 containing subtype than for the β4 containing counterpart, while 20b possesses reversed selectivity. Modeling studies suggest that the spatial distribution of the ligand's atoms around the pharmacophore elements may control their nAChR subtype selectivity.

Original languageEnglish (US)
Pages (from-to)921-924
Number of pages4
JournalJournal of medicinal chemistry
Volume46
Issue number6
DOIs
StatePublished - Mar 13 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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