Drug Design & Discovery, Aptuit Verona srl, Via A Fleming 4, 37135 Verona, Italy.
Expert Opin Ther Pat. 2013 Mar;23(3):363-81. doi: 10.1517/13543776.2013.757593. Epub 2013 Jan 3.
The synthesis and characterization of new highly potent and selective dopamine (DA) D3 receptor antagonists has permitted to characterize the role of the DA D3 receptor in the control of drug-seeking behavior and in the pathophysiology of impulse control disorders and schizophrenia.
In the present review, the authors will first describe most recent classes of DA D3 receptor antagonists by reviewing about 43 patent applications during the 2007 - 2012 period; they will then outline the biological rationale in support of the use of selective DA D3 receptor antagonists in the treatment of drug addiction, impulse control disorders and schizophrenia.
The strongest clinical application and potential for selective DA D3 receptor antagonists lies in the reduction of drug-induced incentive motivation, the attenuation of drug's rewarding efficacy and the reduction in reinstatement of drug-seeking behavior triggered either by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior or stress. The selectivity of these antagonists together with reduced lipophilicity (minimizing unspecific binding), increased brain penetration and improved physico-chemical profile are all key factors for clinical efficacy and safety.
新的高活性和选择性多巴胺（DA）D3 受体拮抗剂的合成和特性研究，使人们能够确定 DA D3 受体在药物寻求行为的控制以及冲动控制障碍和精神分裂症的病理生理学中的作用。
在本综述中，作者首先将通过回顾 2007 年至 2012 年期间的约 43 项专利申请，描述最近的几类 DA D3 受体拮抗剂；然后概述支持使用选择性 DA D3 受体拮抗剂治疗药物成瘾、冲动控制障碍和精神分裂症的生物学基本原理。
选择性 DA D3 受体拮抗剂的最强临床应用和潜力在于减少药物引起的激励动机，减轻药物的奖赏效果，并减少由重新接触药物本身、重新接触以前与药物使用行为相关的环境线索或应激引起的药物寻求行为的复燃。这些拮抗剂的选择性以及降低的亲脂性（最大程度减少非特异性结合）、增加的脑穿透性和改善的物理化学特性都是临床疗效和安全性的关键因素。
