TY - JOUR T1 - Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 340 LP - 349 DO - 10.1124/jpet.115.224071 VL - 354 IS - 3 AU - Martin A. Lewis AU - Lisa Hunihan AU - John Watson AU - Robert G. Gentles AU - Shuanghua Hu AU - Yazhong Huang AU - Joanne Bronson AU - John E. Macor AU - Brett R. Beno AU - Meredith Ferrante AU - Adam Hendricson AU - Ronald J. Knox AU - Thaddeus F. Molski AU - Yan Kong AU - Mary Ellen Cvijic AU - Kristin L. Rockwell AU - Michael R. Weed AU - Angela M. Cacace AU - Ryan S. Westphal AU - Andrew Alt AU - Jeffrey M. Brown Y1 - 2015/09/01 UR - http://jpet.aspetjournals.org/content/354/3/340.abstract N2 - The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol-5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity. ER -