Behavioral Effects of a Novel Allosteric Potentiator of the Dopamine D1 Receptor in Human D1 Knock‐in Mice and Rhesus Monkeys
Authors: Svensson Kjell A , Beck James P , Hao Junliang , Schaus John M , Maren Deanna L , Menezes Michelle M , Falcone Julie F , Anderson Wesley , Knopp Kelly , Adams Benjamin L , Witkin Jeffrey M , Li Xia , Cramer Jeffrey , Harper Alex J , Wafford Keith A , Zhang Linli , Yang Charles R , Bruns Robert F 
Published: November 2023

Allosteric potentiators increase the affinity of endogenousagonist, in effect amplifying physiological control circuits. Because a potentiator should depend onendogenous tone, its effects are predicted to be self‐limiting and less proneto rapid tolerance development compared to direct‐acting agonists. Our objective was to test this hypothesis using DETQ, a novel allosteric potentiator of the dopamine D1 receptor.Although DETQ has high affinity for the human D1 receptor, it is 70‐fold less potent at the mouse and rat D1 receptors, limiting its use as a pharmacological tool in rodents. To overcome this limitation, we created a transgenic knock‐in mouse expressing the human D1 receptor (hD1). Homozygotes showed normal behavior and breeding.After oral dosing, DETQ caused a dose‐dependent 10‐fold increase in locomotor activity in habituated hD1 mice but not in wild‐type mice, implying a requirement for the human D1 receptor. The increase in locomotor activity was blocked by the D1 antagonist SCH39166 and by pretreatment with a high dose of reserpine, indicating that the behavioral response is dependent on endogenous dopamine release. At higher doses, the response to DETQ reached a plateau even though brain concentrations of unbound drug continued to rise. In contrast, the D1 agonists SKF82958 and A‐77636 showed bell‐shaped dose‐response curves, with a profound decrease in locomotor activity at the highest doses. The suppression of locomotor activity at high doses was due to engagement of competing stereotyped behaviors such as intense grooming. The stereotyped behaviors were not seen with DETQ, providing evidence that the response to DETQ is less liable to cause over stimulation. In repeated dosing over four days, the locomotor response to DETQ was maintained, whereas the response to A‐77636 showed rapid tolerance.In hD1 mice treated with a low dose of reserpine, DETQ restored locomotor activity to untreated control levels; this model is relevant to stand‐alone therapy in mild‐to‐moderate Parkinson's disease. Versus a higher dose of reserpine, DETQ acted synergistically with L‐DOPA in restoring locomotor activity. DETQ also increased wakefulness and decreased sleep and was found to be effective in a behavioral despair model. We also compared DETQ with SKF82958 for efficacy in the Y‐maze. While both compounds enhanced the number of arm entries in a dose–dependent fashion, mice treated with DETQ maintained spontaneous alternation even at high doses, whereas mice treated with higher doses of SKF82958 showed an increased prevalence to return to the same arm (asign of cognitive dysfunction). Finally, DETQ increased spontaneous eye blink rate in the rhesus monkey, a response related to central D1 activation.These results confirm that D1 potentiators may possess advantages over D1 agonists for the treatment of Parkinson's disease and other CNS disorders.