Discovery of D1 dopamine receptor positive allosteric modulators: Characterization of pharmacology and identification of residues that regulate species selectivity

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)340-349
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume354
Issue number3
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

Lewis, M. A., Hunihan, L., Watson, J., Gentles, R. G., Hu, S., Huang, Y., Bronson, J., Macor, J. E., Beno, B. R., Ferrante, M., Hendricson, A., Knox, R. J., Molski, T. F., Kong, Y., Cvijic, M. E., Rockwell, K. L., Weed, M. R., Cacace, A. M., Westphal, R. S., ... Brown, J. M. (2015). Discovery of D1 dopamine receptor positive allosteric modulators: Characterization of pharmacology and identification of residues that regulate species selectivity. Journal of Pharmacology and Experimental Therapeutics, 354(3), 340-349. https://doi.org/10.1124/jpet.115.224071