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 Ki values ranging from 0.055 to 0.69nM compared to a Ki value of 0.15nM for compound 1. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors led to identify several agonists and antagonists.