Synthesis and structure–activity relationships of 5-substituted pyridine analogues of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543

In an effort to probe the steric influence of C5 substitution of the pyridine ring on CNS binding affinity, analogues of 1 substituted with a bulky moiety—such as phenyl, substituted phenyl, or heteroaryl—were synthesized and tested in vitro for neuronal nicotinic acetylcholine receptor binding affinity. The substituted analogues exhibited K i values ranging from 0.055 to 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 receptors led to identify several agonists and antagonists.