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Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites

Luderman, Kathryn D.; Conroy, Jennie L.; Free, R. Benjamin; Southall, Noel; Ferrer, Marc; Sanchez-Soto, Marta; Moritz, Amy E.; Willette, Blair K. A.; Fyfe, Tim J.; Jain, Prashi; Titus, Steve; Hazelwood, Lisa A.; Aub�, Jeffrey; Lane, J. Robert; Frankowski, Kevin J.; Sibley, David R.


Kathryn D. Luderman

Jennie L. Conroy

R. Benjamin Free

Noel Southall

Marc Ferrer

Marta Sanchez-Soto

Amy E. Moritz

Blair K. A. Willette

Tim J. Fyfe

Prashi Jain

Steve Titus

Lisa A. Hazelwood

Jeffrey Aub�

Associate Professor

Kevin J. Frankowski

David R. Sibley


The D1 dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. Positive allosteric modulators (PAMs), with their potential for greater selectivity and larger therapeutic windows, may represent a viable drug development strategy, as orthosteric D1 receptor agonists possess known clinical liabilities. We discovered two structurally distinct D1 receptor PAMs, MLS6585 and MLS1082, via a high-throughput screen of the NIH Molecular Libraries program small-molecule library. Both compounds potentiate dopamine-stimulated G protein- and ?-arrestin-mediated signaling and increase the affinity of dopamine for the D1 receptor with low micromolar potencies. Neither compound displayed any intrinsic agonist activity. Both compounds were also found to potentiate the efficacy of partial agonists. We tested maximally effective concentrations of each PAM in combination to determine if the compounds might act at separate or similar sites. In combination, MLS1082 + MLS6585 produced an additive potentiation of dopamine potency beyond that caused by either PAM alone for both ?-arrestin recruitment and cAMP accumulation, suggesting diverse sites of action. In addition, MLS6585, but not MLS1082, had additive activity with the previously described D1 receptor PAM "Compound B," suggesting that MLS1082 and Compound B may share a common binding site. A point mutation (R130Q) in the D1 receptor was found to abrogate MLS1082 activity without affecting that of MLS6585, suggesting this residue may be involved in the binding/activity of MLS1082 but not that of MLS6585. Together, MLS1082 and MLS6585 may serve as important tool compounds for the characterization of diverse allosteric sites on the D1 receptor as well as the development of optimized lead compounds for therapeutic use.


Luderman, K. D., Conroy, J. L., Free, R. B., Southall, N., Ferrer, M., Sanchez-Soto, M., …Sibley, D. R. (2018). Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites. Molecular Pharmacology, 94(4), 1197-1209.

Journal Article Type Article
Acceptance Date Jul 27, 2018
Online Publication Date Oct 1, 2018
Publication Date 2018-01
Deposit Date Apr 22, 2020
Journal Molecular Pharmacology
Print ISSN 0026-895X
Electronic ISSN 1521-0111
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 94
Issue 4
Pages 1197-1209
Public URL
Publisher URL