Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Sep;354(3):340-9.
doi: 10.1124/jpet.115.224071. Epub 2015 Jun 24.

Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity

Martin A Lewis  1 , Lisa Hunihan  1 , John Watson  1 , Robert G Gentles  1 , Shuanghua Hu  1 , Yazhong Huang  1 , Joanne Bronson  1 , John E Macor  1 , Brett R Beno  1 , Meredith Ferrante  1 , Adam Hendricson  1 , Ronald J Knox  1 , Thaddeus F Molski  1 , Yan Kong  1 , Mary Ellen Cvijic  1 , Kristin L Rockwell  1 , Michael R Weed  1 , Angela M Cacace  1 , Ryan S Westphal  1 , Andrew Alt  1 , Jeffrey M Brown  2
Affiliations

Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity

Martin A Lewis et al. J Pharmacol Exp Ther. 2015 Sep.

Abstract

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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Substances

LinkOut - more resources