D3 Receptor Compounds for the Treatment of Psychostimulant Abuse

 描述(由申请人提供)：虽然多巴胺能通路已被明确地与奖赏的强化方面有关，但多巴胺受体亚型在寻求药物行为、恢复、药物渴望和复发的动机中的确切作用仍不清楚。这一应用的假设是，芳酰胺苯基哌嗪类似物与D3多巴胺受体具有高亲和力，并具有不同的D3和D2受体选择性，可以安全地用于戒毒康复计划中的可卡因滥用治疗。基于我们以前的研究获得的信息，我们提出了新的合成策略，通过1)修饰邻位立位药效团(苯基哌嗪部分)和2)将结合和功能研究获得的信息以及吸附、分布、代谢、消除(ADME)研究和PK分析的结果整合到合成设计中，以确定具有期望的药理特征和药代动力学(PK)特性的化合物适合于治疗人类的可卡因滥用。然后，将在大鼠身上测试选定的化合物，以评估它们减轻可卡因相关行为的能力。这项研究有可能导致一种新的治疗可卡因依赖和精神刺激性滥用相关行为的策略。目的1.合成新型D3受体选择性增效剂。我们建议通过合成新型芳酰胺高哌嗪、咪唑烷、氮杂托烷和氮杂石榴烷类似物来修饰苯基哌嗪正构体药效团。目的2.结合和功能选择性的评价。目标1中描述的类似物的亲和力将使用放射性配基结合技术在D1多巴胺、D2样多巴胺(D2、D3和D4)多巴胺、sigma 1和2受体上进行测定。此外，我们的新化合物的内在有效性将通过多种体外功能测试来评估，包括：a)腺酰环化酶抑制；b)有丝分裂；c)MAPK/PERK通路激活；d)arrestin结合。化合物还将在体内测试CFOS的激活、对自发运动的影响以及对旋转机器人性能的影响。目的3.评价用于ADME的选定化合物和药代动力学性质。根据结合和功能选择性图谱(AIM 2)，将使用一组体外ADME和体内PK图谱分析来评估一组D3受体选择性化合物。目的4.评价新合成化合物对可卡因增强、动机和运动功能的影响。将评估选定的一组新化合物(目标1-3)在低和累进比率强化计划下对可卡因自我给药的影响，以及对已熄灭的可卡因寻找行为的恢复的影响。

 DESCRIPTION (provided by applicant): While dopaminergic pathways have been clearly implicated in the reinforcing aspects of reward, the precise role of the dopamine receptor subtypes in motivation for drug seeking behaviors, reinstatement, drug craving and relapse remains unclear. The hypothesis for this application is that arylamide phenylpiperazine analogs, that bind with high affinity at D3 dopamine receptors and varying D3 vs. D2 receptor selectivity, can be used safely for the treatment of cocaine abuse in the context of a drug rehabilitation program. Based upon the information gained from our previous studies, we propose new synthetic strategies to identify compounds with the desired pharmacological profiles and pharmacokinetic (PK) properties appropriate for the treatment of cocaine abuse in humans by 1) modifying the orthosteric pharmacophore (phenylpiperazine moiety) and 2) integrating information obtained from binding and functional studies, as well as findings from adsorption, distribution, metabolic, elimination (ADME) studies and PK analysis into the synthetic design. Select compounds will then be tested in rats to evaluate their ability to attenuate cocaine-associated behaviors. This research has the potential to lead to a new treatment strategy for cocaine dependence and psychostimulant abuse-related behaviors. Aim 1. Synthesis of novel D3 receptor selective compound with increased efficacy. We propose to modify the phenylpiperazine orthosteric pharmacophore by synthesizing panels of novel arylamide homopiperazine, imidazolidine, aza-tropane and aza-granatane analogs. Aim 2. Evaluation of binding and functional selectivity. The affinity of analogs described in Aim 1 will be determined at D1 dopamine, D2-like (D2, D3 and D4) dopamine, sigma 1 and 2 receptors using radioligand binding techniques. In addition, the intrinsic efficacy of our novel compounds will be evaluated using multiple in vitro functional assays including, a) adenylyl cyclase inhibition, b) mitogenesis c) MAPK/pERK pathway activation and d) ¿-arrestin binding. Compounds will also be tested in vivo for cFos activation, effects on spontaneous locomotion and effects on rotarod performance. Aim 3. Evaluation of selected compounds for ADME and pharmacokinetic properties. Based upon binding and functional selectivity profile (Aim 2), a select panel of D3 receptor selective compounds will be evaluated using a battery of in vitro ADME and in vivo PK profiling assays. Aim 4. Evaluate the effects of the newly synthesized compounds on cocaine reinforcement, motivation and motor function. A select panel of novel compounds (Aims 1-3) will be evaluated for their effects on cocaine self-administration under low and progressive ratio reinforcement schedules and on reinstatement of extinguished cocaine seeking behavior.