Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Physiology (Bethesda). 2021 Mar 1;36(2):102-113. doi: 10.1152/physiol.00029.2020.
There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB and CB), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB receptor is overactivated in metabolic alterations, pharmacological blockade of the CB receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB and CB receptors at the peripheral level to be therapeutic targets in metabolic diseases. We focus on the impact of pharmacological intervention and/or silencing on peripheral cannabinoid receptors in organs/tissues relevant for energy homeostasis. Moreover, we provide a perspective on novel therapeutic strategies modulating these receptors. Targeting CB with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB and CB open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB and CB might be possible by developing dual-steric ligands. The future will tell whether these promising strategies result in a renaissance of the cannabinoid receptors as therapeutic targets in metabolic diseases.
迫切需要开发有效的药物来对抗肥胖和 2 型糖尿病的流行。内源性大麻素系统在能量平衡中起着重要作用。它包括大麻素受体 1 和 2（CB1 和 CB2）、称为内源性大麻素的内源性配体及其代谢酶。由于代谢改变使 CB 受体过度激活，因此药理学阻断 CB 受体成为治疗肥胖的有希望的候选药物。然而，由于 CB 受体在中枢神经系统中广泛表达，其负中枢作用阻止了进一步的治疗用途。尽管 CB 受体主要在周围表达，但它在代谢稳态中的作用仍不清楚。这篇综述讨论了在代谢疾病中，外周 CB 和 CB 受体作为治疗靶点的潜力。我们专注于药理学干预和/或沉默对与能量稳态相关的器官/组织中外周大麻素受体的影响。此外，我们提供了一种调节这些受体的新治疗策略的视角。针对外周受限的拮抗剂、中性拮抗剂、反向激动剂或单克隆抗体的 CB 靶向可能是一种成功的策略。CB 激动剂在临床前水平显示出有希望的结果。除了经典的针对正位点的拮抗和激动作用外，CB 和 CB 的最近描述的晶体结构为使用负变构调节剂和正变构调节剂提供了新的治疗干预可能性。通过开发双重立体配体，同时靶向 CB1 和 CB2 可能是可行的。未来将表明这些有前途的策略是否会导致大麻素受体作为代谢疾病的治疗靶点复兴。
