Potent and Highly Selective D3 Ligands for the Treatment of Cocaine Abuse

描述(由申请人提供)：几种不同的证据表明，多巴胺3(D3)亚型受体可能参与了几种药物成瘾的积极奖励机制，包括可卡因、D-苯丙胺和其他精神刺激剂。最近的研究也有力地表明，选择性D3配体可能作为治疗可卡因成瘾、滥用和依赖的新型药物疗法。虽然已经报道了一些选择性的D3配体，但它们中的大多数都没有足够的溶解性来在体内进行评估，并被开发为潜在的有用的治疗药物。此外，尽管一些D3配体在D3受体上表现出高亲和力，并且基于它们的体外数据显示出对D2受体和其他多巴胺受体亚型的良好选择性，但在我们经过充分验证的大鼠体内功能分析中，它们对D3受体相对于D2受体的选择性非常有限。因此，为了进一步阐明D3受体在药物成瘾中的作用，更重要的是开发一种通过调节D3受体来治疗可卡因滥用的新疗法，显然需要具有高体外和体内选择性以及良好的物理化学和药理学特性的有效的D3配体。在这个项目中，我们建议设计和合成具有良好的物理化学和药理学特性的有效和高选择性的D3配体，并对它们在体外和体内的效力、特异性和D3受体的功能以及它们治疗可卡因滥用的潜力进行详细的评估。我们的初步数据清楚地表明，设计有效的、高选择性的、具有良好类药物性质的D3配体用于药物开发是可行的。我们的长期目标是开发一种有效的、高度选择性的D3配体，用于治疗可卡因滥用。为了实现这一目标，我们组建了一个由多学科研究人员组成的团队，他们在计算药物设计和药物化学、多巴胺受体的生化药理学、体内行为药理学以及药物代谢和药物动力学(DMPK)方面具有广泛的专业知识。如果成功开展，我们的研究将使至少一个极有希望的D3配体进入高级临床前开发阶段，作为一种治疗成瘾、依赖和滥用可卡因的新药物疗法。

DESCRIPTION (provided by applicant): Several different lines of evidence suggest that the dopamine 3 (D3) subtype receptor may be involved in the positive rewarding mechanism of the addiction of several drugs, including cocaine, D-amphetamine and other psychostimulants. Recent studies also strongly indicate that selective D3 ligands may have the therapeutic potential as novel pharmacotherapies for the treatment of cocaine addiction, abuse and dependence. Although a number of selective D3 ligands have been reported, most of them have insufficient solubility to be evaluated in vivo and to be developed as potentially useful therapeutic agents. Furthermore, while some D3 ligands show high affinity at the D3 receptor and excellent selectivity over the D2 receptor and other dopamine receptor subtypes based upon their in vitro data, they display very limited selectivity for the D3 receptor over the D2 receptor in our well validated in vivo functional assays in the rat. Hence, potent D3 ligands with high in vitro and in vivo selectivity and favorable physiochemical and pharmacological properties are clearly needed for further elucidation of the role of the D3 receptor in drug addiction and more importantly for the development of a new therapy for the treatment of cocaine abuse through modulation of the D3 receptor. In this project, we propose to design and synthesize potent and highly selective D3 ligands with favorable physiochemical and pharmacological properties and to perform detailed in vitro and in vivo evaluations for their potency, specificity and function at the D3 receptor and their therapeutic potential for the treatment of cocaine abuse. Our preliminary data have clearly demonstrated that it is feasible to design potent and highly selective D3 ligands with excellent drug like properties for drug development. Our long-term goal is to develop a potent and highly selective D3 ligand for the treatment of cocaine abuse. To achieve this goal, we have assembled a multi-disciplinary team consisting of investigators with extensive expertise in computational drug design and medicinal chemistry, biochemical pharmacology of the dopamine receptors, in vivo behavioral pharmacology and drug metabolism and pharmacokinetics (DMPK). Successfully carried out, our research will advance at least one highly promising D3 ligand into advanced preclinical development as a novel pharmacotherapy for addiction, dependence and abuse of cocaine.