The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB₁ than CB₂ and was more potent than Δ9-THC and the N-alkylamides that exhibited CB₂ selective affinity; the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB₁ antagonist, Rimonabant was pulled from commercial markets for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.

由大麻素受体（CB）及其配体，G蛋白和其他效应子参与的有条理的，调控严格的信号转导，共同构成了内源性大麻素系统（ECS）。该系统控制着许多生物学功能，包括细胞增殖，离子转运调节和神经元信息传递。这篇综述将首先检查ECS的生理，简要讨论ECS信号中继中的一些异常，因为这些异常因此与包括神经系统疾病，心血管疾病和癌症在内的全球性疾病有关。虽然内源性配体对于通过ECS分发消息至关重要，但与大量天然和合成的外源性配体的亲和力也存在共性。所以，这篇综述提供了两种类型的外源配体的比较分析，重点是天然产物，因为它们具有更安全的假定功效以及Δ9-四氢大麻酚（Δ9-THC）在揭示ECS中的作用。两种化合物的功效均相同，但值得注意的是联合疗法在不产生不良副作用的情况下达到功效的效果。一个例子是Sativex，它在临床前模型中治疗亨廷顿舞蹈病（HD）方面显示出了希望，从而使其可以过渡到当前的临床研究。尽管 一个例子是Sativex，它在临床前模型中治疗亨廷顿舞蹈病（HD）方面显示出了希望，从而使其可以过渡到当前的临床研究。尽管 一个例子是Sativex，它在临床前模型中治疗亨廷顿舞蹈病（HD）方面显示出了希望，从而使其可以过渡到当前的临床研究。尽管Δ9-THC在体外和临床前治疗神经退行性疾病的功效，其精神作用限制了其在治疗进食障碍方面的临床适用性。因此，我们建议进一步研究其他化合物及其组合，例如对CB _1的结合亲和力比CB _2大，比Δ9-THC和对CB ₂有选择性的N-烷基酰胺更有效的三萜，α，β-amyrin亲和力 后者可以探索为外围专有的ECS调制。合成炭黑₁ 利莫那班（Rimonabant）拮抗剂被从商业市场上撤出，用于治疗糖尿病，但是其类似物SR144528可能是实现这一目标的理想先导分子，而HU-210和Org27569也是有希望的合成小分子。