Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

用于治疗药物成瘾的多巴胺 D3 受体拮抗剂：临床前模型

• 批准号: 8148522
• 负责人: Eliot Gardner
• 金额: $ 29.36万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148522
• 关键词: Cues; Dopamine; Dose; Drug Addiction; Drug Design; Pharmaceutical Preparations; Pre-Clinical Model; dopamine D3 receptor

During the period 01 Oct 09 to 30 Sept 10, significant progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel preferential dopamine D3 receptor antagonist S33138 emulates the putative anti-addiction, anti-craving, and anti-relapse efects that we have previously seen with our lead proof-of-concept dopamine D3 receptor antagonist SB277011A. Specifically, we found that S33138 attenuates intravenous cocaine self-administration, attenuates relapse to cocaine-seeking behavior (using the reinstatement animal model) triggered by cocaine, and significantly attenuates drug-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques) produced by cocaine. These effects were seen at low to moderate doses of S33138. At high doses, dopamine D2 antogonist-like effects were observed. These findings add further weight to our previous suggestions that selective dopamine D3 receptor antagonists may be useful in the treatment of drug addiction. With regard to the effects observed with high doses of S33138, we found them to be similar to those that we previously observed with the putative selective D3 antagonist BP897 - and we conclude that the effects of both S33138 and BP897 are likely attributable to a combination of D3 and D2 receptor antagonism. During the reporting period, we also studied the selective dopamine D3 receptor antagonist PG01037. We found that PG01037 shares a very similar profile of action in animal models of addiction as our lead compound SB277011A - PG01037 does not alter intravenous methamphetamine self-administration when the cocaine is available under low-effort high-payoff conditions, PG01037 significantly lowers the progressive-ratio breakpoint for intravenous methamphetamine self-administration under progressive-ratio reinforcement conditions (reflecting decreased incentive motivation to self-administer methamphetamine), PG01037 significantly inhibits methamphetamine-associated cue-triggered relapse to drug-seeking behavior in animals behaviorally extinguished and pharmacologically weaned from methamphetamine, and PG01037 significantly inhibits methamphetamine-enhanced brain stimulation reward. These findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, and that the D3 antagonist PG01037 appears to possess the same anti-addiction profile observed with our lead proof-of-concept compounds SB277011A and NGB2904.

在09年10月1日至9月10日期间，该研究项目取得了重大进展。 我们发现，新型的优先多巴胺D3受体拮抗剂S33138封锁了脑多巴胺D3受体S33138，仿真了我们以前在我们以前在我们以前与我们的铅概念验证多巴胺D3受体抗体抗体抗体抗体抗体抗体抗体抗体抗体拮抗剂SB2777777777011a一起观察到的推定的抗毒性，抗捕获和抗透明的效率。 具体而言，我们发现S33138减弱了可卡因自我给药，减轻了可卡因触发的可卡因寻求行为（使用恢复动物模型）的复发（使用恢复动物模型），并显着减弱了药物增强的大脑奖励（如电脑刺激性奖励奖励电式技术所评估的，可用于评估。 这些作用以低至中剂量的S33138观察到。 在高剂量下，观察到多巴胺D2 antogonist样作用。 这些发现进一步增加了我们以前的建议，即选择性多巴胺D3受体拮抗剂可能有助于治疗药物成瘾。 关于高剂量S33138观察到的效果，我们发现它们与以前在推定的选择性D3拮抗剂BP897中观察到的效果相似，我们得出结论，S33138和BP897的效果可能与D3和D2受体拮抗抗体的组合可能属于S33138和BP897。 在报告期间，我们还研究了选择性多巴胺D3受体拮抗剂PG01037。 We found that PG01037 shares a very similar profile of action in animal models of addiction as our lead compound SB277011A - PG01037 does not alter intravenous methamphetamine self-administration when the cocaine is available under low-effort high-payoff conditions, PG01037 significantly lowers the progressive-ratio breakpoint for intravenous methamphetamine self-administration under PG01037显着抑制甲基苯丙胺相关的提示触发的动机，对动物的毒品触发行为抑制甲基苯丙胺相关的复发，并在行为上灭绝的动物中，PG01037显着抑制了甲基苯丙胺相关的甲基苯丙胺触发行为，并从甲基乙酰氨基甲基甲基甲基甲基甲基脱落的甲基甲基氨基甲基和PGG01037显着抑制了甲基苯丙胺相关的复发，PG01037显着抑制了甲基苯丙胺相关的提示复发，PG01037显着抑制甲基苯丙胺相关的促进甲基苯丙胺的复发 - 报酬。 这些发现表明，多巴胺D3受体拮抗剂在人类药物成瘾中可能具有抗增添，反捕获和抗透明疗效，并且D3拮抗剂PG01037似乎具有与我们的较高量验证剂验证剂的较高剂量验证型SB277011AA和NGB22904。