Soler-Cedeño Omar, Keegan Bradley M, Alton Hannah, Bi Guo-Hua, Linz Emily, Vogt Caleb D, Gogarnoiu Emma S, Shi Lei, Newman Amy Hauck, Xi Zheng-Xiong
Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
Br J Pharmacol. 2025 Jul;182(13):2997-3016. doi: 10.1111/bph.70021. Epub 2025 Mar 27.
Preclinical studies suggest that highly selective dopamine D receptor (DR) 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 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.
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.
BRET functional assays indicated that cariprazine and ESG-1-60 are D receptor-preferring partial agonists, while ESG-1-61 is a D 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.
Novel D 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.
临床前研究表明，高选择性多巴胺D受体（DR）拮抗剂或部分激动剂有望用于治疗物质使用障碍。然而，它们在减少可卡因自我给药方面效果有限，这是一个主要缺点。本研究调查了卡立普唑（D受体偏好性部分激动剂）及其类似物ESG-1-60和ESG-1-61在减少可卡因摄取和觅药行为方面是否具有增强的疗效。
体外生物发光共振能量转移（BRET）实验用于表征卡立普唑及其类似物的功能效力。静脉注射可卡因自我给药和复吸模型用于评估减少可卡因摄取和觅药行为的疗效。光学颅内自我刺激（oICSS）程序评估对多巴胺依赖性行为的影响。旷场运动、口服蔗糖自我给药和条件性位置偏爱用于评估潜在的不良副作用。
BRET功能测定表明，卡立普唑和ESG-1-60是D受体偏好性部分激动剂，而ESG-1-61是D受体偏好性拮抗剂/反向激动剂。在固定比率和累进比率强化方案下，这三种化合物均抑制可卡因自我给药，并减少雄性和雌性大鼠中可卡因诱导的觅药行为复吸。这些化合物未改变运动行为，但抑制了蔗糖摄取和多巴胺依赖性oICSS。卡立普唑和ESG-1-61产生了显著的位置厌恶，而ESG-1-60没有。长期给予ESG-1-60可抑制可卡因自我给药。
新型D受体偏好性化合物ESG-1-60和ESG-1-61在各种强化条件下，在减少可卡因摄取和觅药方面非常有效。ESG-1-60作为治疗可卡因使用障碍的新药物疗法值得进一步研究，因为它在这些模型中有效且缺乏不良行为影响。
