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首页> 外文期刊>European Journal of Pharmacology: An International Journal >Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists.
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Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists.

机译：抑郁和焦虑症的中央CRH系统-来自CRH1受体拮抗剂的临床研究的证据。

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摘要

Basic and clinical studies provide convincing evidence that altered stress hormone regulation frequently observed in depression and anxiety are caused by elevated secretion of the hypothalamic neuropeptides corticotrophin releasing hormone (CRH) and vasopressin. CRH predominantly acts through CRH(1) receptors to produce a number of anxiety- and depression-like symptoms, which resulted in extensive validation of CRH(1) receptors as potential drug target. A number of orally available nonpeptidergic small molecules capable to pass the blood-brain barrier have been discovered; only some of these compounds entered clinical development. Here, we summarize results from clinical studies of two CRH(1) receptor antagonists. In the first study originally designed as a safety and tolerability trial in major depression, it was observed that the CRH(1) receptor antagonist NBI-30775/R121919 has a clinical profile comparable to the antidepressant paroxetine. In a second study the effect of another CRH(1) receptor antagonist, NBI-34041, upon stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound reduced the stress-elicited secretion of cortisol. Both compounds, however, did not impair the CRH-induced release of ACTH and cortisol rejecting the possibility that the peripheral stress hormone system is impaired by CRH(1) receptor antagonists. From these studies we conclude that both CRH(1) receptor antagonists have psychotropic effects unrelated to their neuroendocrine action, which is in line with behavioral data obtained from transgenic mice. The results of the clinical studies underscore that CRH(1) receptor antagonists represent promising novel therapeutics in the psychopharmacology of depression and anxiety.
机译：基础和临床研究提供了令人信服的证据，表明抑郁症和焦虑症中经常观察到的应激激素调节改变是由下丘脑神经肽促肾上腺皮质激素释放激素（CRH）和加压素的分泌增加引起的。 CRH主要通过CRH（1）受体产生许多焦虑和抑郁样症状，从而广泛验证了CRH（1）受体作为潜在药物靶标的可能性。已经发现了许多能够通过血脑屏障的口服非肽能小分子。这些化合物中只有一部分进入临床开发。在这里，我们总结了两种CRH（1）受体拮抗剂的临床研究结果。在最初设计为重度抑郁症的安全性和耐受性试验的第一项研究中，观察到CRH（1）受体拮抗剂NBI-30775 / R121919具有与抗抑郁药帕罗西汀相当的临床特征。在第二项研究中，研究了另一种CRH（1）受体拮抗剂NBI-34041对心理社会应激源的应激激素分泌的影响。施用该化合物减少了应激引起的皮质醇分泌。但是，这两种化合物都不会损害CRH诱导的ACTH和皮质醇释放，从而消除了CRH（1）受体拮抗剂损害周围应激激素系统的可能性。从这些研究中我们得出结论，两种CRH（1）受体拮抗剂均具有与它们的神经内分泌作用无关的精神作用，这与从转基因小鼠获得的行为数据一致。临床研究结果强调，CRH（1）受体拮抗剂在抑郁症和焦虑症的心理药理学中代表有希望的新型疗法。

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