ESG-1-60 and ESG-1-61: novel dopamine D3 receptor-preferring partial
agonists/antagonists that inhibit cocaine taking and seeking without
motor effect
Abstract
Background and Purpose: Preclinical studies suggest that highly
selective dopamine D3 receptor (D3R) antagonists or partial agonists
hold promise for treating substance use disorders (SUD). However, their
limited effectiveness in reducing cocaine self-administration is a major
drawback. This study investigated whether cariprazine (a D3R-preferring
partial agonist) and its analogs ESG-1-60 and ESG-1-61 have enhanced
efficacy in reducing cocaine-taking and -seeking behavior. Experimental
Approach: In vitro BRET experiments were used to characterize the
functional efficacies of cariprazine and its analogs. Intravenous
cocaine self-administration and reinstatement models were used to
evaluate efficacy in reducing cocaine-taking and -seeking behavior.
Optical intracranial self-stimulation (oICSS) procedures assessed
effects on DA-dependent behavior. Open-field locomotion, oral sucrose
self-administration, and conditioned place-preference were used to
evaluate potential unwanted side effects. Key Results: BRET functional
assays indicated that cariprazine and ESG-1-60 are D3R-preferring
partial agonists, while ESG-1-61 is a D3R-preferring antagonist/inverse
agonist. All three compounds inhibited cocaine self-administration under
both fixed-ratio and progressive-ratio reinforcement schedules and
reduced cocaine-induced reinstatement of drug-seeking behavior in both
male and female rats. The compounds did not alter locomotor behavior but
suppressed sucrose intake and DA-dependent oICSS. Cariprazine and
ESG-1-61 produced significant place aversion, while ESG-1-60 did not.
Chronic administration of ESG-1-60 inhibited cocaine
self-administration. Conclusions and Implications: Novel D3R-preferring
compounds ESG-1-60 and ESG-1-61 are highly effective in reducing cocaine
taking and seeking under various reinforcement conditions. ESG-1-60
warrants further investigation as a new pharmacotherapy for treating
cocaine use disorder due to its effectiveness in these models and lack
of unwanted behavioral effects.