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

描述（由申请人提供）：几条不同的证据表明多巴胺3 （D3）亚型受体可能参与几种药物成瘾的积极奖励机制，包括可卡因，d -安非他明和其他精神兴奋剂。最近的研究也强烈表明，选择性D3配体可能具有治疗可卡因成瘾，滥用和依赖的新型药物疗法的治疗潜力。尽管已经报道了一些选择性D3配体，但它们中的大多数都没有足够的溶解度，无法在体内进行评估，也无法开发成潜在的有用的治疗剂。此外，尽管一些D3配体在体外实验中显示出对D3受体的高亲和力和对D2受体和其他多巴胺受体亚型的极好选择性，但在我们对大鼠的体内功能实验中，它们对D3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，更重要的是为了开发一种通过调节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理化和药理学特性的强效D3配体。在这个项目中，我们建议设计和合成具有良好物理化学和药理学特性的强效和高选择性D3配体，并对其在D3受体上的效力、特异性和功能及其治疗可卡因滥用的潜力进行详细的体外和体内评估。我们的初步数据清楚地表明，设计具有优异药物样特性的强效和高选择性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、高选择性的D3配体来治疗可卡因滥用。为了实现这一目标，我们组建了一个多学科的团队，包括在计算药物设计和药物化学、多巴胺受体的生化药理学、体内行为药理学和药物代谢和药代动力学（DMPK）方面具有广泛专业知识的研究人员。如果成功开展，我们的研究将推动至少一种极具前景的D3配体进入临床前开发阶段，作为一种治疗可卡因成瘾、依赖和滥用的新型药物疗法。

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.