NPY-Like Agonists and Antagonists for CNS YL Receptors

Neuropeptide Y (NPY) activates at least three receptor subtypes with central and peripheral localization (Y1, Y2, and Y3). The human Y1 receptor, linked to various CNS disorders including anxiety, depression, bulimia, and cocaine addition, has been cloned and targeted by Synaptic Pharmaceutical Corporation for the development of orally available, centrally active, non-peptide drugs. In Phase I, we will coordinate multidisciplinary resources from molecular biology, medicinal chemistry, molecular modeling, and pharmacology. To start, we will channel the Y1 receptor, currently studied in transient expression systems, into a stably transformed cell line optimal for functional analysis of NPY-like agonists and antagonists. Simultaneously, we will exploit a chemical screening strategy based on prior examination of non-peptide compounds with gross structural similarity to NPY and also to benextramine, an NPY-like adrenergic drug. This strategy has resulted in the identification of several structural leads with affinity for NPY receptors. These compounds will now be modified and re-evaluated in more extensive pharmacological assays based on radioligand competition and functional coupling to adenylate cyclase activity. Long term goals will be realized in Phase II when compounds will be tested in increasingly relevant bioassays for anxiety, feeding, and other CNS disorders.