Serendipity rediscovered — an oxymoron or rational drug design: Studies on subtype selective BzR/GABAergic ligands

MEDI 208

James M. Cook, capncook@uwm.edu1, Harry June2, Elise Weerts3, Micheal L. Van Linn1, Donna Platt4, Tim DeLorey5, Miroslav Savic6, and Terry Clayton1. (1) Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee Wisconsin, Milwaukee, WI 53211, (2) School of Medicine, University of Maryland, (3) Behavioral Biology Research Center, John Hopkins Bayview Medical Center, (4) Behavioral Biology, Harvard Medical School, (5) Molecular Research Institute, Moltech Corporation, (6) Department of Pharmacology, University of Belgrade
Recently we have developed a series of subtype selective ligands for BzR/GABAergic receptors. In this series of agents, 3-PβC•HCl and βCCt have been shown to decrease alcohol self-administration in alcohol preferring rats (June, et. al.) and more recently in baboons (Weerts, et. al.) and rhesus monkeys (Platt, et. al.), respectively. In a different study, α5 subtype selective ligands have been developed which bind with potent affinity only at α5 BzR subtypes and enhance cognition in animal models. Moreover, these ligands exhibit weak inverse agonist activity at α5 subtypes and very weak agonist activity at α2 subtypes. The lead compound was able to reverse the scopolamine-induced deficits in cognition in the trace fear conditioning paradigm in contextual memory but not in audio cued memory (DeLorey et. al.). Recent results in these areas will be presented.
 

Smissman Award Symposium
9:00 AM-12:30 PM, Monday, August 20, 2007 BCEC -- 210 B/C, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007