Synthesis and evaluation of nicotine analogs as neuronal nicotinic acetylcholine receptor ligands

A series of 3'-, 4'-, and 5'-substituted nicotine analogs have been synthesized and evaluated as ligands of the neuronal nicotinic acetylcholine receptor. The compounds prepared were found to have binding affinities ranging from 4 to 3500 nM. The results indicate that only a small substituent or functionality is well tolerated at the C4' position of nicotine and that binding affinity is affected by both steric and electronic properties of the substituent. On the other hand, the C3' and C5' positions seem to be the more sensitive toward bulky substituents. The best compound, 4'-methylnicotine, is nearly equipotent to nicotine. It possesses the most favorable binding affinity.