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

ABSTRACT: 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 β-arrestin-mediated signaling and increase the affinity of dopamine for the D

SUBMITTER: Luderman KD 

PROVIDER: S-EPMC6117505 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature