Endocannabinoids acting via CB1 receptors (CB1R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB1R antagonists for the treatment of obesity. Although the first-in-class CB1R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB1Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by 'second generation' peripherally restricted CB1R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB1R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel 'third generation' hybrid inhibitors of peripheral CB1R and inducible NO synthase were tested in mouse models of liver and pulmonary fibrosis where their antifibrotic efficacy was found to exceed the efficacy of drugs that inhibit only one of these targets. In this review, we will discuss the challenges and opportunities offered by second and third generation CB1R antagonists and their potential therapeutic uses.

中文翻译：

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第二代和第三代 CB1R 拮抗剂的治疗潜力。

通过 CB1 受体 (CB1R) 起作用的内源性大麻素在调节能量稳态方面发挥着关键作用，这是开发用于治疗肥胖症的 CB1R 拮抗剂的药物开发的基本原理。尽管一流的 CB1R 拮抗剂利莫那班被证明可有效减轻肥胖及其多种心脏代谢并发症，但由于中枢神经系统介导的神经精神副作用，它已退出临床使用，这阻止了整类此类药物的进一步治疗开发化合物。与大脑相比，CB1R 在参与调节能量稳态的外周器官（包括肝脏、骨骼肌、脂肪组织和内分泌胰腺）中以低但功能水平的水平表达。在最近的临床前研究中，“第二代”选择性靶向这些受体 外周限制性 CB1R 拮抗剂在肥胖和糖尿病的啮齿动物模型中复制了利莫那班的代谢益处，而不会引起 CNS 介导的副作用。CB1R 活性增加也会导致复杂的多因素疾病，例如各种形式的组织纤维化，其治疗可能受益于同时参与多个治疗目标。因此，在肝和肺纤维化小鼠模型中测试了外周 CB1R 和诱导型 NO 合酶的新型“第三代”杂化抑制剂，发现它们的抗纤维化功效超过了仅抑制这些靶标之一的药物的功效。在这篇综述中，我们将讨论第二代和第三代 CB1R 拮抗剂及其潜在治疗用途所带来的挑战和机遇。