Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954).
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.
Croston
Glenn E
GE
ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, California 92121, USA.
Olsson
Roger
R
Currier
Erika A
EA
Burstein
Ethan S
ES
Weiner
David
D
Nash
Norman
N
Severance
Daniel
D
Allenmark
Stig G
SG
Thunberg
Linda
L
Ma
Jian-Nong
JN
Mohell
Nina
N
O'Dowd
Brian
B
Brann
Mark R
MR
Hacksell
Uli
U
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
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