Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, MD, USA.
Indivior Inc., Richmond, VA, USA.
Curr Top Behav Neurosci. 2023;60:157-201. doi: 10.1007/7854_2022_347.
Over three decades of evidence indicate that dopamine (DA) D receptors (DR) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective DR antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, DR are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the DR system. Third, the synthesis and characterization of highly potent and selective DR antagonists/partial agonists have further strengthened the role of the DR in SUD. Based on extensive preclinical and preliminary clinical evidence, the DR shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective DR antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective DR antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.
三十多年的证据表明，多巴胺 (DA) D 受体 (DR) 参与了觅药行为的控制，并且可能在物质使用障碍 (SUD) 的病理生理学中发挥重要作用。选择性 DR 拮抗剂/部分激动剂对 SUD 治疗有效的期望基于以下关键观察结果。首先，DR 分布在属于中脑边缘 DA 系统的战略区域，如腹侧纹状体、中脑和腹侧苍白球，这些区域与由药物相关线索呈现控制的行为有关。其次，反复接触滥用药物会导致 DR 系统发生神经适应性变化。第三，高度有效和选择性的 DR 拮抗剂/部分激动剂的合成和表征进一步加强了 DR 在 SUD 中的作用。基于广泛的临床前和初步临床证据，DR 作为 SUD 药物治疗开发的靶点显示出希望，因为它们有可能：(1) 调节药物自我给药的动机，(2) 破坏对药物相关刺激的反应性，这些刺激在重新暴露于药物本身、药物相关环境线索或应激时触发觅药行为的恢复中发挥关键作用。用于评估选择性 DR 拮抗剂/部分激动剂对临床相关受体占有率的 PET 配体的可用性、可靠剂量的定义以及使用人类实验室模型的前景，可能会进一步指导临床概念验证研究的设计。迫切需要进行关键的临床试验，以更快速地推进该靶点获得监管批准。最后，发现高度选择性的 DR 拮抗剂，如 R-VK4-116 和 R-VK4-40，单独或在与羟考酮或可卡因存在时，不会对周围生物标志物或心血管效应产生不利影响，这表明这类药物在安全治疗精神兴奋剂和/或阿片类药物使用障碍方面具有巨大潜力。
