The goal of this project is to develop nicotine agonists that selectively modulate central dopaminergic function via a-conotoxin Mll-sensitive nicotinic acetylcholine receptors (nAChRs). Nicotinic receptors of this subtype mediate nicotine-induced dopamine release in the nigrostriatal dopaminergic system. Selective activation of these nAChRs therefore constitutes a potentially useful strategy for the management of PD. In preliminary experiments, we have discovered a substituted chroman that stimulates release of dopamine from rat striatal membranes without evoking the release of acetylcholine (ACh) from rat cortex. Moreover, electrophysiologic recordings of Xenopus oocytes expressing human nAChRs confirm the preferential activation of a3b2 nAChRs by this compound. The objective of the present investigation is thus to expand the pool of lead compounds in this structural class. Specifically, we propose to synthesize 8 related substituted chromans and coumarins. These compounds will be screened for 1) binding to alpha3beta2, alpha6/alpha3beta2, alpha4beta2, alpha7, alpha3beta4 and alpha1beta1delta nAChRs; 2) ability to activate these nAChR subtypes in heterelogous expression systems; and 4) their ability to stimulate a-conotoxin MIl-sensitive striatal dopamine release, cortical ACh release and cation (Rb-86) efflux. The most potent and selective activators of a-conotoxin MIl-sensitive striatal dopamine release will be used as the starting point for an intensive lead optimization effort.
