Instituto de Quimica Medica (IQM-CSIC). C/ Juan de la Cierva, 3, 28006, Madrid, Spain.
Centro de Investigaciones Biologicas (CIB-CSIC). C/ Ramiro de Maeztu, 9, 28040, Madrid, Spain.
Curr Med Chem. 2019;26(18):3300-3340. doi: 10.2174/0929867325666180226095132.
The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.
20 世纪 90 年代初发现了大麻素受体，1990 年克隆了 CB1，1993 年克隆了 CB2，以及出现了选择性和强效的大麻类似物，这些都只能用能够与它们结合的内源性配体的存在来解释。因此，第一个大麻素受体（CB1）的特征和克隆导致了第一个内源性大麻素，花生四烯酰乙醇胺（AEA）的分离和特征，两年后，随后又鉴定了一类称为脂肪酸酯 2-花生四烯酰甘油（2-AG）的脂质递质家族。内源性大麻素系统是一个复杂的信号系统，包括跨膜内源性大麻素受体、它们的内源性配体（内源性大麻素）、特定的摄取机制以及与其生物合成和降解相关的酶系统。内源性大麻素系统参与了中枢和外周神经系统中广泛的生物过程，包括记忆、学习、神经元发育、应激和情绪、食物摄入、能量调节、外周代谢以及通过内分泌系统调节激素平衡。在这种情况下，本文将回顾大麻素受体作为阿尔茨海默病和其他不太知名的疾病（包括多发性硬化症、骨代谢和脆性 X 综合征等）的治疗靶点的潜在治疗应用。通过研究作为单一药物和多靶点药物的大麻素激动剂来探讨治疗应用，突出 CB2 受体激动剂。
