Anand Jessica P, Montgomery Deanna
Department of Pharmacology, Medical School and the Edward F. Domino Research Center, University of Michigan, Ann Arbor, MI, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Handb Exp Pharmacol. 2018;247:21-51. doi: 10.1007/164_2018_104.
The opioid receptor system plays a major role in the regulation of mood, reward, and pain. The opioid receptors therefore make attractive targets for the treatment of many different conditions, including pain, depression, and addiction. However, stimulation or blockade of any one opioid receptor type often leads to on-target adverse effects that limit the clinical utility of a selective opioid agonist or antagonist. Literature precedent suggests that the opioid receptors do not act in isolation and that interactions among the opioid receptors and between the opioid receptors and other proteins may produce clinically useful targets. Multifunctional ligands have the potential to elicit desired outcomes with reduced adverse effects by allowing for the activation of specific receptor conformations and/or signaling pathways promoted as a result of receptor oligomerization or crosstalk. In this chapter, we describe several classes of multifunctional ligands that interact with at least one opioid receptor. These ligands have been designed for biochemical exploration and the treatment of a wide variety of conditions, including multiple kinds of pain, depression, anxiety, addiction, and gastrointestinal disorders. The structures, pharmacological utility, and therapeutic drawbacks of these classes of ligands are discussed.
阿片受体系统在情绪、奖赏和疼痛调节中起主要作用。因此，阿片受体成为治疗许多不同病症（包括疼痛、抑郁和成瘾）的有吸引力的靶点。然而，刺激或阻断任何一种阿片受体类型通常会导致靶向不良反应，从而限制了选择性阿片激动剂或拮抗剂的临床应用。文献先例表明，阿片受体并非孤立发挥作用，阿片受体之间以及阿片受体与其他蛋白质之间的相互作用可能产生临床上有用的靶点。多功能配体有可能通过激活特定受体构象和/或因受体寡聚化或串扰而促进的信号通路，从而以减少的不良反应引发预期结果。在本章中，我们描述了几类与至少一种阿片受体相互作用的多功能配体。这些配体已被设计用于生化探索以及治疗多种病症，包括多种疼痛、抑郁、焦虑、成瘾和胃肠道疾病。讨论了这些类配体的结构、药理效用和治疗缺陷。
