Synthesis of Heterocyclic Substituted Pyridine Analogs as Potential Therapeutics for Neurodegenerative Diseases

The potential therapeutic benefit of nicotinic ligands in a variety of neurodegenerative pathologies involving the CNS has energized research efforts to develop nicotinic acetylcholine receptor (nAChR) subtype-selective ligands. In particular, there has been a concerted effort to develop nicotinic compounds with selectivity for CNS nAChRs as potential pharmacological tools in the management of these disorders. The characterization of other novel nicotinic ligands such as epibatidine. showing a marked increase in potency at nAChRs, has provided additional support for the development of potent, selective ligands at individual nAChR subtypes. We have developed and studied a number of nicotinic compounds to identify potential candidates exhibiting such selectivity. In the present study, we report the synthesis and biological evaluations of some azabicyclic and azatricyclic nicotine analogs to decipher the relationship among steric requirements of the nicotine's pyrrolidine ring system, binding affinity and subtype-selectivity.