2002•Journal of Medicinal ChemistryOpen access
Discovery of the First Nonpeptide Agonist of the GPR14/Urotensin-II Receptor: 3-(4-Chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954)
Glenn E Croston, Roger M. Olsson, Erika A. Currier, Ethan S. Burstein, David M. Weiner, Norman R. Nash, Daniel L. Severance, Stig G Allenmark, Linda Thunberg, Jian‐Nong Ma, Nina Mohell, Brian F. O’Dowd, Mark R. Brann, Uli Hacksell
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Abstract
A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)- 1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a selective nonpeptidic druglike UII receptor agonist, (+)-1 will be useful as a pharmacological research tool and a potential drug lead.