D3 Receptor Compounds for the Treatment of Psychostimulant Abuse

描述（由申请人提供）：用于治疗精神兴奋剂滥用的D3受体化合物。本申请是根据RFA-DA-07-006提交的，标题为“药物成瘾潜在治疗剂的设计、合成和临床前测试”。本研究计划描述了a)合成，b)体外药理表征和c)体内评价新型D3多巴胺受体选择性拮抗剂，部分激动剂和激动剂作为治疗可卡因滥用的潜在治疗剂。我们的假设是，对伏隔核D3多巴胺受体的刺激在精神兴奋剂的强化特性中起着关键作用。我们进一步假设，D3多巴胺受体亚型选择性化合物有潜力作为新一代基于D3受体的药物治疗药物，用于治疗和/或管理滥用精神兴奋剂的个体。由于D2和D3多巴胺受体亚型的结合位点高度同源，因此很难开发出真正的D3受体选择性化合物。然而，我们最近发现了一组取代的苯基哌嗪化合物，它们对D3多巴胺受体亚型具有不同程度的内在活性，具有50 - 30倍的选择性。因此，我们开始了解这些化合物的结构如何影响D2和D3多巴胺受体亚型的结合和功能选择性。在目标1中，我们将合成一组新化合物，作为我们持续目标的一部分，以生成最大化D3受体选择性的化合物，同时a)最小化logp值（< 3.0），这是预测药物穿过血脑屏障的能力，b)具有激活几种不同信号通路的不同能力（功能选择性）。在目标2中，我们建议对D3选择性化合物的结合和内在活性进行体外药理学评估。这将包括以前研究的化合物和有限数量的新化合物（目标1）我们的新化合物将通过a)结合试验来评估D2和D3受体的内在活性，以检查高和低亲和力状态的选择性，b)腺苷酸环化酶抑制试验，c) GIRK电生理试验和d)有丝分裂试验。在目标3中，我们将评估我们的新化合物的体内功效，以减轻a)精神兴奋剂依赖性增加的运动活动和b)可卡因的自我给药。固定比率（FR）和累进比率（PR）时间表都将使用。此外，将检查化合物对恢复已消失的可卡因寻求行为的影响。本研究项目的总体目标是确定a)决定结合和功能选择性的化合物的结构元素，b)哪些功能特性/特性可以预测啮齿动物药物成瘾模型的行为功效。

DESCRIPTION (provided by applicant): D3 Receptor Compounds for the Treatment of Psychostimulant Abuse. This application is submitted in response to RFA-DA-07-006 entitled Design, Synthesis, and Preclinical Testing of Potential Treatment Agents for Drug Addiction. This research proposal describes the a) synthesis, b) in vitro pharmacological characterization and c) in vivo evaluation of novel D3 dopamine receptor selective antagonists, partial agonists and agonists as potential therapeutic agents for the treatment of cocaine abuse. Our hypothesis is that stimulation of the D3 dopamine receptor in the nucleus accumbens plays a pivotal role in the reinforcing properties of psychostimulants. We further hypothesize that D3 dopamine receptor subtype selective compounds have potential as a new generation of D3 receptor-based pharmacotherapeutics for the treatment and/or management of individuals who abuse psychostimulants. Because of the high degree of homology between the binding sites of the D2 and D3 dopamine receptor subtypes, it has been difficult to develop authentic D3 receptor selective compounds. However, we have recently identified a panel of substituted phenyl-piperazine compounds that are > 30-fold selective for the D3 dopamine receptor subtype with varying degrees of intrinsic activity. Therefore, we are beginning to understand how the structure of these compounds influences binding and functional selectivity at D2 and D3 dopamine receptor subtypes . In Aim 1 we will synthesize a panel new compounds as part of our continuing goal to generate compounds which maximize D3 receptor selectivity while a) minimizing log P values (< 3.0), which are predictive of a drug's ability to cross the blood brain barrier and b) having varying ability to active several different signaling pathways (functional selectivity). In Aim 2 we propose to undertake an in vitro pharmacological assessment of the binding and intrinsic activity of D3 selective compounds. This will include compounds from previous studies and the limited number of new compounds (Aim 1) Our novel compounds will be evaluated for intrinsic activity at both D2 and D3 receptors using a) binding assays to examine selectivity for high and low affinity states, b) an adenylyl cyclase inhibition assay, c) a GIRK electrophysiology assay and d) a mitogenic assay. In Aim 3 we will evaluate the in vivo efficacy of our novel compounds for the ability to attenuate the a) psychostimulant-dependent increased locomotor activity and b) self-administration of cocaine. Both fixed ratio (FR) and a progressive ratio (PR) schedules will be used. In addition, compounds will be examined for their effects on reinstatement of extinguished cocaine-seeking behavior. The overall goal of this research project is to determine a) the structural elements of our compounds that determine binding and functional selectivity and b) which functional property/properties are predictive of behavioral efficacy in the rodent model of drug addiction.