促肾上腺皮质激素释放因子Ⅰ型受体:抗抑郁药物的新靶标

Corticotrophin releasing factor type-1 receptor:a novel target for the treatment of depression

抑郁和焦虑患者常伴随应激激素调节失常,这与下丘脑神经肽促肾上腺皮质激素释放因子(CRF)和精氨酸加压素分泌过多密切相关。CRF主要通过激动促肾上腺皮质激素释放因子Ⅰ型(CRF1)受体诱导抑郁或焦虑样症状,众多研究表明CRF1受体是新型抗抑郁药的潜在靶标。目前已研发出很多基于此靶标的非肽类小分子化合物,但只有一部分进入临床试验,包括NBI-30775/R121919和NBI-34041等。值得注意的是,此类化合物显效与动物的应激水平和自身焦虑程度有关,即CRF1受体拮抗剂可在不影响下丘脑-垂体-肾上腺轴基础活性情况下对抗CRF介导的病理性应激反应,从而提示其副作用可能较低。总之,小分子CRF1受体拮抗剂可能成为治疗应激相关精神疾病的新方法。本文重点综述CRF1受体作为新靶标在抑郁症治疗中的潜在应用。

Basic and clinical studies provide convincing evidence that altered stress hormone regulation frequently observed in depression and anxiety is caused by elevated secretion of the hypothalamie neuropeptides corticotrophin releasing factor （CRF） and vasopressin. CRF predominantly acts through CRF1 receptor producing a number of anxiety- and depression-like symptoms, which results in extensive validation of CRF1 receptors as a potential drug target. A number of oral nonpeptidergic small molecules capa ble to pass the blood-brain barrier have been discovered, but only some of them enter into clinical development, including NBI-30775/R121919 and NBI-34041. Interestingly, the anti-depressant-like effects of these compounds in rodents seem to be contingent upon levels of stress or innate emotionality. These findings support th~ notion that CRF1 receptor antagonists might be capable of blocking pathological CRFmediated stress response without producing undesired side-effects caused by the general inhibition of hy- pothalamus-pituitary-adrenal system activity. Clinical studies underscore that CRF1 receptor antagonists represent promising novel therapeutics in the treatment of stress-related mental disorders. Here we summarize the potential utility of CRFI receptor as novel target in the treatment of depression.