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首页> 外文期刊>Addiction biology >YQA14: A novel dopamine D 3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D 3 receptor-knockout mice
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YQA14: A novel dopamine D 3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D 3 receptor-knockout mice

机译：YQA14：一种新型多巴胺D 3受体拮抗剂，可抑制可卡因在大鼠和小鼠中的自我给药，但在抑制D 3受体的小鼠中不起作用

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摘要

The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti-addiction pharmacotherapeutic agents in animal models of drug addiction. SB-277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB-277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB-277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with K i-High (0.68 × 10 -4 nM) and K i-Low (2.11 nM), and displays 150-fold selectivity for D3 over D2 receptors and 1000-fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25-25 mg/kg) or SB-277011A (12.5-25 mg/kg) significantly and dose-dependently reduced intravenous cocaine self-administration under both low fixed-ratio and progressive-ratio reinforcement conditions in rats, while failing to alter oral sucrose self-administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB-277011A significantly inhibited basal and cocaine-enhanced locomotion in rats. Finally, both D3 antagonists dose-dependently inhibited intravenous cocaine self-administration in wild-type mice, but not in D3 receptor-knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti-addiction profile as SB-277011A, and deserves further study and development.
机译：多巴胺（DA）D3受体被认为与药物奖励和成瘾有关，而D3受体拮抗剂作为药物成瘾动物模型中潜在的抗成瘾药物治疗剂已显示出非凡的前景。 SB-277011A是此类模型中特征最明确的D3受体拮抗剂。但是，药代动力学和毒性问题排除了SB-277011A在人体中的潜在用途。我们在这里报告了一种新型的D3受体拮抗剂YQA14，其表现出与SB-277011A类似的药理特性。体外受体结合试验表明，YQA14在人克隆的D3受体上具有两个结合位点，分别为K i-High（0.68×10 -4 nM）和K i-Low（2.11 nM），并且对D3的选择性超过150倍D2受体和D3的选择性是其他DA受体的> 1000倍。在低固定比例和渐进比例强化条件下，大鼠全身施用YQA14（6.25-25 mg / kg）或SB-277011A（12.5-25 mg / kg）并显着剂量依赖性地降低了静脉内可卡因的自我给药，同时不能改变口服蔗糖的自我给药和运动活性，提示药物奖励的选择性抑制。但是，当药物剂量增加到50 mg / kg时，YQA14和SB-277011A显着抑制了大鼠的基础和可卡因增强的运动。最后，两种D3拮抗剂在野生型小鼠中剂量依赖性地抑制了静脉注射可卡因的自我给药，但在D3受体敲除小鼠中却没有，这表明它们的作用是由D3受体阻滞介导的。这些发现表明，YQA14具有与SB-277011A类似的抗成瘾特性，值得进一步研究和开发。

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