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

Abstract

Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator 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]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3–20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30–240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists.

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

“…Dopamine receptors constitute a family of G protein–coupled receptors (GPCRs) that are widely expressed in the brain and contribute to diverse neuronal functions. In particular, the D1-like receptor subfamily, which includes the dopamine receptor type 1 (D1R) and D5R, plays a key role in locomotor activity ( Svensson et al, 2017 ) and cognitive and social behaviors ( Cools, 2008 ; Homberg et al, 2016 ). The effects of D1/D5R stimulation by agonists have been thoroughly studied in behavioral tests in rodents ( Zahrt et al, 1997 ; Stubbendorff et al, 2019 ) and primates ( Sawaguchi and Goldman-Rakic, 1991 ; Arnsten et al, 2015 ).…”

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

“…D 1 PAMs, due to their mechanism of action, have the potential to avoid the adverse effects seen excessive D 1 receptor activation. Consistent with this D 1 PAMs, unlike D 1 agonists, induced changes in locomotion in a humanized mouse line that plateaued at high doses without inducing stereotypies (Svensson et al, 2016). The recent discovery of both D 2 - and D 1 -selective allosteric scaffolds represents an important advance and hopefully will lead to optimized compounds that can provide therapeutically desirable outcomes with fewer side-effects than those observed with DA receptor agonists and antagonists.…”

The Role of Zebrafish and Laboratory Rodents in Schizophrenia Research

“…A non-selective agonist apomorphine binds to both types of receptors, alhough with a higher affinity to D 2 and selective activation of D 2 can have a stronger impact on locomotor activity in some strains than selective activation of D1, which may suggest a higher impact of D 2 on locomotion. However in some mutant animals selective agonists of D 2 do not have an effect on locomotion ( 166 ) and insterestingly, activation of D1 receptors can induce hyperlocomotion without other set of common symptoms, stereotypy, suggesting a specific tool in reseach as well as therapy ( 293 ). Both dopamine receptors are highly involved in schizophrenia, however, hyperlocomotion in animal models can be also triggered directly via NMDA antagonists, which was confirmed on dopamine-deficient mice lacking tyrosine hydroxylase.…”