Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, P.O. Box 922, 3000 Leuven, Belgium.
Int J Mol Sci. 2020 Jul 17;21(14):5064. doi: 10.3390/ijms21145064.
Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.
大麻素受体（CB1 和 CB2）作为内源性大麻素系统的一部分，在许多人类生理和病理条件中起着关键作用。因此，人们做出了巨大的努力来开发 CB1 和 CB2 的配体，产生了数以百计的植物源和合成大麻素，它们表现出不同的亲和力，可用于治疗各种疾病。然而，这些配体中只有少数被临床应用。最近，由于冷冻电子显微镜的强大功能，大麻素受体的更详细的结构信息得以揭示，这有助于加速基于结构的药物发现。同时，来自动物源的新型肽类大麻素也已经出现，它们在与大麻素受体相关的治疗效果方面具有潜力。从天然产物的角度来看，预计将从各种天然来源和物种中发现更多新型大麻素，并将其预测为有前途的药物先导化合物，如动物毒液，它构成了调节包括电压门控和配体门控离子通道、G 蛋白偶联受体（如 CB1 和 CB2）在内的多种靶标的毒素的真正药典，具有惊人的亲和力和选择性。因此，人们相信，从研究生活在地球上的物种的生物多样性开始发现新型大麻素是一个未知的领域。
