Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor that act at diverse binding sites

Authors

• KD Luderman
• JL Conroy
• RB Free
• N Southall
• M Ferrer
• M Sanchez-Soto
• AE Moritz
• BKA Willette
• TJ Fyfe
• P Jain
• S Titus
• LA Hazelwood
• J Aubé
• JR Lane
• KJ Frankowski
• DR Sibley

Abstract

The D1 dopamine receptor (D1R) is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer’s 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 D1R agonists possess clinical liabilities. We discovered two structurally distinct D1R PAMs, MLS6585 and MLS1082, via a high throughput screen of the NIH Molecular Libraries Program. Both compounds potentiated dopamine-stimulated G-protein- and β-arrestin-mediated signaling and increased the affinity of dopamine for D1R with low micromolar potencies. Neither compound displayed intrinsic agonist activity. Both compounds potentiated 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 β-arrestin recruitment and cAMP accumulation, suggesting diverse sites of action. In addition, MLS6585, but not MLS1082, had additive activity with the previously described D1R PAM “compound B,” suggesting that MLS1082 and compound B may share a binding site. A point mutation in D1R (R130Q) abrogated MLS1082 activity without affecting that of MLS6585, suggesting this residue may be involved in the binding/activity of MLS1082, but not MLS6585. Together, MLS1082 and MLS6585 may serve as important tool compounds for the characterization of diverse allosteric sites on D1R as well as the development of optimized lead compounds for therapeutic use.

Scientific Focus Area: Molecular Pharmacology

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