The goal of this Phase I STTR project is to identify novel negative allosteric modulators of the nicotinic acetylcholine receptor. This project seeks to partner the drug discovery technology of the Promiliad Biopharma with the expertise of Professor Dennis McKay to identify novel and subtype selective negative allosteric modulators of the nicotinic acetylcholine receptor. We believe that such compounds could provide a significant improvement in available therapies for smoking addiction. Work supported with this grant will examine the Promiliad Biopharma compound database to identify small molecules that fit a previously identifed nicotinic acetylcholine receptor pharmacophore. Compounds that fit the pharmacophore will be examined in a variety of pharmacological assays to identify negative allosteric modulators of three subtypes of the nicotinic acetylcholine receptor. In addition to the in silico screening of the Promiliad compound library, Promiliad Biopharma will prepare libraries of previously identified negative allosteric modulators of the nicotinic acetylcholine receptor. These libraries will make use of Promiliad's drug discovery technology in order to prepare a diverse and novel set of analogues. In addition to identifying a new selective negative allosteric modulator of the nicotinic acetylcholine receptor, this project will also allow Promilad to test the hypothesis that the Promiliad drug discovery technology can be used for the idenfication of a variety of therapeutic agents. PUBLIC HEALTH RELEVANCE: The goal of this Phase I STTR project is to identify novel negative allosteric modulators of the nicotinic acetylcholine receptor. This project seeks to partner the drug discovery technology of the Promiliad Biopharma with the expertise of Professor Dennis McKay to identify novel and subtype selective negative allosteric modulators of the nicotinic acetylcholine receptor. We believe that such compounds could provide a significant improvement in available therapies for smoking addiction.