Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.
Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.
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DOI：
10.1111/j.1749-6632.2009.05149.x
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发表时间：
2010-02
影响因子：
5.2
通讯作者：
Newman AH
中科院分区：
文献类型：
--
作者：
Heidbreder CA;Newman AH
反复接触滥用药物会产生长期的分子和神经化学变化，这些变化可以解释成瘾的核心特征，如强迫性寻求和服用药物以及复发的风险。越来越多的成瘾药物的新分子和细胞靶点已经被确定，并且在成瘾动物模型中将这些靶点与特定行为表型相关联方面正在取得快速进展。在这种情况下，多巴胺（DA）D3受体在啮齿类动物和人脑中的表达模式和这种模式的变化，在响应药物滥用的主要贡献直接研究工作的选择性DA D3受体拮抗剂的发展。越来越多的临床前证据表明，这些化合物实际上可以调节自我给药的动机，并破坏药物相关的线索诱导的渴望。本报告将分为三个部分。首先，临床前的证据支持选择性DA D3受体拮抗剂在药物成瘾的动物模型的疗效将进行审查。这里不讨论混合DA D2/D3受体拮抗剂的作用，因为这些化合物中的大多数对D3受体的选择性较低，并且它们的功效特征主要与对D2受体的功能性拮抗作用以及与其他神经递质系统的可能相互作用有关。其次，将分析药物化学在识别和优化选择性DA D3受体拮抗剂和部分激动剂方面的主要进展。第三，将讨论从临床前疗效研究到药物成瘾适应症的概念验证研究的转化研究。
Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.
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影响因子：
7.6
作者：
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