Nicotine addiction remains a major problem and is the leading cause of preventable mortality worldwide. Nicotine's reinforcing and rewarding effects are thought to be due to its binding to neuronal nicotinic acetylcholine receptors (nAChR) in the ventral tegmental area (VTA) of the midbrain and ?4?2 nAChR subtype has been identified as a key receptor for the modulation of nicotine addiction. Hence selective modulation of ?4?2 nAChRs is an effective strategy for finding treatment for nicotine abuse. Varenicline, a clinically used smoking cessation agent, is a partial agonist at ?4?2 nAChRs. Dihydro-?-erythroidine (DHBE), a key constituent of the erythrina alkaloids isolated from trees and shrubs belonging to the genus Erythrina, is a potent ?4?2 nAChR antagonist with selectivity towards the ?2 subunit. Although DHBE is an excellent research standard and probe for nAChR behavioral and basic research, there has been no systematic medicinal chemistry effort done on DHBE to understand its structure activity relationships for selective modulation of ?4?2 nAChRs. Part of the reason behind this is the unavailability of a suitable synthetic route to the erythroidine core of DHBE. Moreover, it is no longer commercially available in significant amounts. Therefore, the goal of this proposal is to develop a viable enantiomeric synthesis of DHBE to obtain it in sufficient quantities for research and enable a medicinal chemistry campaign to understand its structure activity relationships. 1
This work is designed to synthesize and identify novel, potent and selective probes for nicotinic acetylcholine receptors involved in nicotine addiction. The compounds that will be discovered in this research will help in understanding the structure activity relationships for binding and selectivity at these receptors and will help in guiding future drug development for treatment of nicotine addiction. 1
