Development of novel nicotinic receptor mediated therapeutic agents: Synthesis and biological evaluation of novel epibatidine analogues.

摘要

Neuronal nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels, and have long been the target for the development of therapeutic agents for tobacco addiction, smoking cessation, muscle relaxation and antihypertension. Recently, nAChRs have been identified as potential targets for the development of new therapeutic agents for the treatment of a number of other central nervous system (CNS) diseases and disorders. (−)-Epibatidine, which was isolated from the skin of the Ecuadorian poison dart frog, Epipedobates tricolor, exhibits remarkable non-opioid analgesic properties. However, it is toxic at doses only slightly higher than its effective analgesic dose.; In an effort to search for more selective neuronal nicotinic acetylcholine receptor analgesics that have less toxicity and adverse side effects relative to epibatidine, five novel series of epibatidine analogues with 7-azabicyclo[2.2.1 ]heptane ring system or 8-azabicyclo[3.2.1]octane ring system were synthesized and evaluated in vitro as potential potent selective nAChR ligands. New synthetic methods were developed for the syntheses of these novel epibatidine analogues. Their structural features associated with the molecular recognition by nAChRs in the brain were systematically investigated in vitro paradigms. Those analogues which were found to exhibit potent or otherwise interesting binding affinity at nAChRs were then tested in vivo to assess the efficacy of the compounds. The structure-activity relationship (SAR) studies of these analogues offer some interesting insights into the elucidation of the neuronal nAChR pharmacophore and will be useful in the further studies aimed at development of selective nAChR therapeutic agents.