YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice.
YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice.
复制标题
DOI：
10.1111/j.1369-1600.2011.00317.x
复制
发表时间：
2012-03
影响因子：
3.4
通讯作者：
Gardner EL
中科院分区：
文献类型：
--
作者：
Song R;Yang RF;Wu N;Su RB;Li J;Peng XQ;Li X;Gaál J;Xi ZX;Gardner EL
多巴胺 (DA) D3 受体被认为在药物奖赏和成瘾中发挥重要作用，D3 受体拮抗剂在药物成瘾动物模型中显示出作为潜在抗成瘾药物治疗剂的非凡前景。 SB-277011A 是此类模型中特征最明确的 D3 受体拮抗剂。然而，SB-277011A 在人体中的潜在用途因药代动力学和毒性问题而被排除。我们在此报告了一种新型 D3 受体拮抗剂 YQA14，其药理学特性与 SB-277011A 相似。体外受体结合测定表明，YQA14 在人类克隆的 D3 受体上有两个结合位点，分别为 Ki-High (0.68 × 10−4 nM) 和 Ki-Low (2.11 nM)，并且对 D3 的选择性比 D2 受体高 150 倍，对 D3 的选择性比其他 DA 受体高 1000 倍。在大鼠中，在低固定比例和渐进比例强化条件下，全身给予 YQA14 (6.25–25 mg/kg) 或 SB-277011A (12.5–25 mg/kg) 显着且剂量依赖性地减少静脉注射可卡因自我给药，同时未能改变口服蔗糖自我给药和运动活性，表明药物奖励的选择性抑制。然而，当药物剂量增加至 50 mg/kg 时，YQA14 和 SB-277011A 显着抑制大鼠的基础运动和可卡因增强的运动。最后，两种 D3 拮抗剂剂量依赖性地抑制野生型小鼠静脉内可卡因的自我给药，但在 D3 受体敲除小鼠中则不然，这表明它们的作用是通过 D3 受体阻断介导的。这些研究结果表明，YQA14 具有与 SB-277011A 相似的抗成瘾特性，值得进一步研究和开发。
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 Ki-High (0.68 × 10−4 nM) and Ki-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.
登录
查看更多内容
影响因子：
7.6
作者：
Di Ciano, P;Underwood, RJ;Everitt, BJ
通讯作者：
Everitt, BJ
影响因子：
7.6
作者：
Andreoli, M;Tessari, M;Heidbreder, CA
通讯作者：
Heidbreder, CA
影响因子：
4
作者：
Maggio, Roberto;Millan, Mark J.
通讯作者：
Millan, Mark J.
影响因子：
7.3
作者：
Macdonald, GJ;Branch, CL;Ashby, CR
通讯作者：
Ashby, CR
影响因子：
2.3
作者：
Ashby, CR;Paul, M;Hagan, JJ
通讯作者：
Hagan, JJ