Structure-activity studies on 2-methyl-3-(2(S)- pyrrolidinylmethoxy)pyridine (ABT-089): An orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties

Nan Horng Lin, David E. Gunn, Keith B. Ryther, David S. Garvey, Diana L. Donnelly-Roberts, Michael W. Decker, Jorge D. Brioni, Michael J. Buckley, A. David Rodrigues, Kennan G. Marsh, David J. Anderson, Jerry J. Buccafusco, Mark A. Prendergast, James P. Sullivan, Michael Williams, Stephen P. Arneric, Mark W. Holladay

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63 Scopus citations

Abstract

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

Original languageEnglish
Pages (from-to)385-390
Number of pages6
JournalJournal of Medicinal Chemistry
Volume40
Issue number3
DOIs
StatePublished - Jan 31 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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