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

Abstract

The D 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 D receptor agonists possess known clinical liabilities. We discovered two structurally distinct D 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 D 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 D receptor PAM "Compound B," suggesting that MLS1082 and Compound B may share a common binding site. A point mutation (R130Q) in the D 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 D receptor as well as the development of optimized lead compounds for therapeutic use.

Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor

“…Arg9 also produced sustained interaction with Ala129 of TM3 in all simulations ( Figure 6 A and Supplementary Figure S2A ). These ICL2 residues have been reported to form an allosteric site in other GPCRs [ 17 , 18 , 19 , 20 ].…”

“…Positive allosteric binding sites of GPCRs have been identified in the past [ 18 , 30 ]. However, recent studies have fully characterized the potential of positive allosteric modulators in multiple GPCRs using in vitro and in silico approaches [ 31 , 32 , 33 ].…”

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia

“…As a PAM of the dopamine D 1 receptor, ASP4345 may have fewer off-target effects because of its selectivity toward dopamine D 1 receptors [ 9 , 10 ]. Additionally, ASP4345 has the potential to effectively ameliorate CIAS without the development of commonly observed side effects associated with dopamine D 1 agonists, such as hypotension and seizures, because it enhances ambient dopaminergic tone rather than activating dopamine D 1 receptors independent of dopamine cell firing and dopamine release from terminals [ 10 – 12 ]. ASP4345 was well tolerated in animal studies and healthy volunteers, which prompted further clinical development of this compound.…”

Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors

“…Recent data also implicate D 5 R in working memory and prefrontal cortex function ( Carr et al., 2017 ). Accordingly, D 1 R agonists (many of which are also D 5 R agonists) and positive allosteric modulators are being investigated as putative therapeutics for the treatment of cognitive deficits, e.g., in Alzheimer’s disease, schizophrenia, and Parkinson’s disease ( Lewis et al., 2015 ; Bruns et al., 2018 ; Luderman et al., 2018 ; Yang et al., 2018 ).…”