Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在本报告所述期间，对该项目进行了少量的实验室工作。此外，在本报告所述期间，积压的关于该项目的实验室调查结果已提前到出版阶段。首先，使用一个新的动物行为模型，我们报告了我们的铅概念验证多巴胺D3受体拮抗剂化合物SB277011A减少了C57BL/J6小鼠暴饮式的酒精消耗。第二，我们报道了SB277011A减弱了药物或食物剥夺应激诱导的可卡因诱导的条件位置偏爱在实验大鼠中的重新激活。第三，我们报告了SB277011A显著加速了与可卡因诱导的位置偏好相关的环境线索的消失。第四，我们报告了SB277011A不会改变大鼠的巴甫洛夫条件性接近行为(手势跟踪与目标跟踪)。第五，我们报道了一系列新的和新颖的4-苯基哌嗪，它们具有非常高的多巴胺D3受体亲和力和/或选择性。化合物19抑制羟考酮诱导的小鼠多动症，并抑制羟考酮诱导的运动敏化。此外，化合物19可剂量依赖性地抑制羟考酮诱导的大鼠条件性位置偏爱。第六，我们报道了左旋四氢巴马汀和小剂量纳曲酮的组合构成了一种很有前途的防止复发的可卡因寻找行为的新疗法。

During the present reporting period, modest laboratory work was conducted on this project. In addition, a backlog of laboratory findings on this project were brought forward to the publication stage during this reporting period. First, using a new additional animal behavioral model, we reported that our lead proof-of-concept dopamine D3 receptor antagonist compound SB277011A decreases binge-like consumption of ethanol in C57BL/J6 mice. Second, we reported that SB277011A attenuates drug- or food-deprivation stress-induced reactivation of the expression of cocaine-induced conditioned place preference in laboratory rats. Third, we reported that SB277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in laboratory rats. Fourth, we reported that SB277011A does not alter Pavlovian conditioned approach behaviors in rats (sign-tracking versus goal-tracking). Fifth, we reported on a new and novel series of 4-phenylpiperazines with exceptionally high dopamine D3 receptor affinities and/or selectivities. Compound 19 of this new chemical series inhibited oxycodone-induced hyperlocomotion in mice, and inhibited oxycodone-induced locomotor sensitization. In addition, pretreatment with compound 19 dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference in laboratory rats. Sixth, we reported that a combination of levo-tetrahydropalmatine and low dose naltrexone constitutes a promising new therapy for prevention of relapse to cocaine-seeking behavior.