title: Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954).
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.
authors.affiliation: ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, California 92121, USA.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Croston
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.forename: Erika A
authors.initials: EA
authors.lastname: Currier
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.forename: David
authors.initials: D
authors.lastname: Weiner
authors.forename: Norman
authors.initials: N
authors.lastname: Nash
authors.forename: Daniel
authors.initials: D
authors.lastname: Severance
authors.forename: Stig G
authors.initials: SG
authors.lastname: Allenmark
authors.forename: Linda
authors.initials: L
authors.lastname: Thunberg
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.forename: Nina
authors.initials: N
authors.lastname: Mohell
authors.forename: Brian
authors.initials: B
authors.lastname: O'Dowd
authors.forename: Mark R
authors.initials: MR
authors.lastname: Brann
authors.forename: Uli
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D000818:Animals; D002839:Chromans / Q000737:chemistry* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D051379:Mice; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C468786:3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one; D002839:Chromans; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human