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ESG-1-60 and ESG-1-61: novel dopamine D3 receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking without motor effect
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  • Omar Soler-Cedeno,
  • Bradley Keegan,
  • Hannah Alton,
  • Guo-hua Bi,
  • Emily Linz,
  • Caleb Vogt,
  • Emma Gogarnoiu,
  • Lei Shi,
  • Amy Hauk Newman,
  • Zheng-Xiong Xi
Omar Soler-Cedeno
Nation Institutes on Drug Abuse, National Institutes of Health
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Bradley Keegan
Nation Institutes on Drug Abuse, National Institutes of Health
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Hannah Alton
Nation Institutes on Drug Abuse, National Institutes of Health
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Guo-hua Bi
National Institute on Drug Abuse Intramural Research Program
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Emily Linz
Nation Institutes on Drug Abuse, National Institutes of Health
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Caleb Vogt
Nation Institutes on Drug Abuse, National Institutes of Health
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Emma Gogarnoiu
Nation Institutes on Drug Abuse, National Institutes of Health
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Lei Shi
Nation Institutes on Drug Abuse, National Institutes of Health
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Amy Hauk Newman
Nation Institutes on Drug Abuse, National Institutes of Health
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Zheng-Xiong Xi
Nation Institutes on Drug Abuse, National Institutes of Health

Corresponding Author:[email protected]

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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.
30 Sep 2024Submitted to British Journal of Pharmacology
01 Oct 2024Submission Checks Completed
01 Oct 2024Assigned to Editor
01 Oct 2024Review(s) Completed, Editorial Evaluation Pending
02 Oct 2024Reviewer(s) Assigned