Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders.

The dopamine D1 receptor plays an important role in motor activity, reward, and cognition. Efforts to develop D1 agonists have been mixed due to poor drug-like properties, tachyphylaxis, and inverted U-shaped dose-response curves. Recently, positive allosteric modulators (PAMs) for the dopamine D1 receptor were discovered and initial pharmacological profiling has suggested that several of the above issues could be addressed with this mechanism. This paper presents an overview of key findings for DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one), which is currently the only D1 PAM for which published in vivo data is available. In vitro studies showed selective potentiation of the human D1 receptor without significant allosteric agonist effects. Due to a species difference in affinity for DETQ, transgenic mice expressing the human D1 receptor (hD1 mice) were used in vivo. In contrast to D1 agonists, DETQ increased locomotor activity over a wide dose-range without inverted U-shaped dose response or tachyphylaxis. DETQ also reversed hypo-activity in mice with dopamine depletion due to reserpine pretreatment, suggesting potential for treatment of motor symptoms in Parkinson's disease. Potential pro-cognitive effects were supported by improved performance in the novel object recognition task, enhanced release of cortical acetylcholine and histamine, and increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB. In addition, DETQ enhanced wakefulness in EEG studies and decreased immobility in the forced-swim test. Together, these results provide support for potential utility of D1 PAMs in the treatment of several neuropsychiatric disorders. LY3154207, a close analog of DETQ, is currently in phase 2 clinical trials.