Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA; email:
Departments of Pharmaceutical Sciences and Biological Chemistry, University of California, Irvine, California 92697, USA.
Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:483-507. doi: 10.1146/annurev-pharmtox-052220-021800. Epub 2021 Sep 13.
The endocannabinoids are lipid-derived messengers that play a diversity of regulatory roles in mammalian physiology. Dysfunctions in their activity have been implicated in various disease conditions, attracting attention to the endocannabinoid system as a possible source of therapeutic drugs. This signaling complex has three components: the endogenous ligands, anandamide and 2-arachidonoyl--glycerol (2-AG); a set of enzymes and transporters that generate, eliminate, or modify such ligands; and selective cell surface receptors that mediate their biological actions. We provide an overview of endocannabinoid formation, deactivation, and biotransformation and outline the properties and therapeutic potential of pharmacological agents that interfere with those processes. We describe small-molecule inhibitors that target endocannabinoid-producing enzymes, carrier proteins that transport the endocannabinoids into cells, and intracellular endocannabinoid-metabolizing enzymes. We briefly discuss selected agents that simultaneous-ly interfere with components of the endocannabinoid system and with other functionally related signaling pathways.
内源性大麻素是脂质衍生的信使分子，在哺乳动物生理学中发挥着多种调节作用。其活性的功能障碍与各种疾病状况有关，这使得内源性大麻素系统成为治疗药物的可能来源，引起了人们的关注。该信号转导复合物有三个组成部分：内源性配体，大麻素和 2-花生四烯酰基甘油（2-AG）；一组产生、消除或修饰这些配体的酶和转运蛋白；以及介导其生物学作用的选择性细胞表面受体。我们提供了内源性大麻素形成、失活和生物转化的概述，并概述了干扰这些过程的药理学药物的特性和治疗潜力。我们描述了针对内源性大麻素产生酶、将内源性大麻素转运到细胞内的载体蛋白以及细胞内内源性大麻素代谢酶的小分子抑制剂。我们简要讨论了同时干扰内源性大麻素系统成分和其他功能相关信号通路的选定药物。
