Synthesis and structure-activity relationships of 5-substituted pyridine analogues of 3-[2-((S)-pyrrolidinyl)methoxyl pyridine, A-84543: A potent nicotinic receptor ligand

In an effort to probe the steric influence of C5 substitution of the pyridi ne ring on CNS binding affinity, analogues of 1 substituted with a bulky mo iety--such as phenyl, substituted phenyl, or heteroaryl--were synthesized a nd tested in vitro for neuronal nicotinic acetylcholine receptor binding af finity. The substituted analogues exhibited K-i values ranging from 0.055 t o 0.69 nM compared to a K-i value of 0.15 nM for compound 1. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine recepto rs led to identify several agonists and antagonists. (C) 2001 Elsevier Scie nce Ltd. All rights reserved.