Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在本报告所述期间，对这个项目进行了少量的实验室工作。此外，在本报告所述期间，积压的关于这个项目的实验室调查结果已提前到出版阶段。首先，使用一种新的动物行为模型，我们报告了我们的主要概念验证多巴胺D3受体拮抗剂化合物SB277011A减少C57BL/J6小鼠的酒精暴饮暴食。其次，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好表达的再激活。第三，我们报道了SB277011A显著加速了实验室大鼠对可卡因诱导的位置偏好相关的环境线索的灭绝。第四，我们报道了SB277011A不会改变大鼠的巴甫洛夫条件趋近行为（信号跟踪与目标跟踪）。第五，我们报道了一个新的和新颖的系列4-苯基哌嗪具有异常高的多巴胺D3受体亲和力和/或选择性。化合物19抑制氧可酮诱导的小鼠过度运动，抑制氧可酮诱导的运动致敏。此外，化合物19预处理对实验鼠羟考酮诱导的条件性位置偏好的获得具有剂量依赖性。第六，我们报道了左旋四氢巴马汀和低剂量纳曲酮联合使用是预防可卡因寻求行为复发的一种有希望的新疗法。

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.