ESG-1-60 and ESG-1-61: Novel dopamine D(3) receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents.

BACKGROUND AND PURPOSE: Preclinical studies suggest that highly selective dopamine D(3) receptor (D(3)R) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self-administration is a major drawback. This study investigated whether cariprazine (D(3) receptor-preferring partial agonist) and its analogues ESG-1-60 and ESG-1-61 have enhanced efficacy in reducing cocaine-taking and cocaine-seeking behaviour. EXPERIMENTAL APPROACH: In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self-administration and reinstatement models were used to evaluate efficacy in reducing cocaine-taking and cocaine-seeking behaviour. Optical intracranial self-stimulation (oICSS) procedures assessed effects on dopamine-dependent behaviour. 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 D(3) receptor-preferring partial agonists, while ESG-1-61 is a D(3) receptor-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 behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine-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 D(3) receptor-preferring compounds ESG-1-60 and ESG-1-61 were highly effective in reducing cocaine-taking and cocaine-seeking, under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects.