Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity

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 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.

An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

“…Efficacy in the nonhuman primate has also been confirmed using the spontaneous eye-blink model (Bruns et al, submitted for publication). Interestingly, the lower affinity of the Bristol-Myers Squibb D1 potentiator “Compound B” (Lewis et al, 2015) for the rat receptor was traced to an R130Q mutation that is limited to the rodent clade (http://www.uniprot.org/). …”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Unfortunately dihydrexidine, which is only moderately selective for D 1 over D 5 , has poor bioavailability and is rapidly metabolized, limiting the clinical utility of this compound. Excitingly, new D 1 -selective PAMs have recently been developed that demonstrate enhanced specificity over D 5 receptors (Lewis et al, 2015). D 1 PAMs, due to their mechanism of action, have the potential to avoid the adverse effects seen excessive D 1 receptor activation.…”

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

“…A D 1 positive allosteric modulator (PAM) would enhance the endogenous actions of DA at D 1 R, and recently, the first published preclinical breakthrough in this area was reported for two series of PAMs (see Figure 4) that are active in vitro (148). One of the compounds was selective for D 1 R, but had much lower activity at the murine vs. the human D 1 R. A patent from Eli-Lilly also reports an additional chemotype for D 1 PAMs that potentiate relevant in vivo signals including locomotor activity and release of acetylcholine in PFC (149).…”