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明确涉及奖励的强化方面，但多巴胺受体亚型在寻求药物行为、复吸、药物渴望和复发动机中的确切作用仍不清楚。本申请的假设是，以高亲和力结合D3多巴胺受体并改变D3与D2受体选择性的芳基酰胺苯基哌嗪类似物可以安全地用于在药物康复计划的背景下治疗可卡因滥用。基于我们以前的研究所获得的信息，我们提出了新的合成策略，以鉴定具有所需药理学特征和药代动力学（PK）性质的化合物，其适合于治疗人类可卡因滥用，通过1）修饰正构药效团（苯基哌嗪部分）和2）整合从结合和功能研究获得的信息，以及从吸附，分布，代谢，将ADME研究和PK分析引入合成设计中。然后将在大鼠中测试选定的化合物，以评估其减弱可卡因相关行为的能力。这项研究有可能为可卡因依赖和精神兴奋剂滥用相关行为提供新的治疗策略。目标1.具有增加功效的新型D3受体选择性化合物的合成。我们建议通过合成新的芳基酰胺高哌嗪，咪唑烷，氮杂托烷和氮杂石榴烷类似物的面板来修改苯基哌嗪正构药效团。目标2.结合和功能选择性的评价。将使用放射性配体结合技术测定目标1中所述的类似物对D1多巴胺、D2样（D2、D3和D4）多巴胺、σ 1和σ 2受体的亲和力。此外，我们的新化合物的内在功效将使用多种体外功能测定来评估，包括a）腺苷酸环化酶抑制，B）有丝分裂发生，c）MAPK/pERK途径活化和d）抑制蛋白结合。还将在体内测试化合物的cFos活化、对自发运动的影响和对旋转杆性能的影响。目标3。评价所选化合物的ADME和药代动力学性质。基于结合和功能选择性特征（目的2），将使用一系列体外ADME和体内PK特征分析试验评价一组选定的D3受体选择性化合物。目标4。评估新合成的化合物对可卡因强化、动机和运动功能的影响。将评价一组选定的新型化合物（目标1 - 3）在低和渐进比例强化方案下对可卡因自我给药的影响以及对恢复已消退的可卡因寻求行为的影响。

 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.