Vasopressin antagonists as anxiolytics and antidepressants: recent developments.
Vasopressin antagonists as anxiolytics and antidepressants: recent developments.
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DOI：
10.2174/157488908784534586
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发表时间：
2008-06-01
期刊：
影响因子：
--
通讯作者：
Koppel, Gary A
中科院分区：
文献类型：
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作者：
Simon, Neal G;Guillon, Christophe;Koppel, Gary A
一个令人信服的情况下，加压素（AVP）拮抗剂作为一种新的治疗类压力相关的情感性疾病的治疗的潜在效用已经出现了基于抑郁症的个人，在焦虑和抑郁症的动物模型中的观察结果，并在慢性压力下的下丘脑-垂体-肾上腺（HPA）轴调节的变化的理解。加压素拮抗剂作为焦虑和抑郁症药物治疗的科学基础包括：1）在受影响的人和焦虑和抑郁的动物模型中伴随慢性应激的HPA功能的神经适应和失调，2）认识到AVP而不是促肾上腺皮质激素释放因子（CRF）驱动与慢性心理应激相关的HPA功能，3）加压素V1 a和V1 b受体在涉及HPA调节和社会行为控制的边缘系统区域中的CNS定位，和4）临床前数据显示在用作抗焦虑和抗抑郁活性筛选的动物模型中的功效。公共卫生需要新的药物治疗与压力有关的情感疾病是有据可查的。仅在美国，焦虑和抑郁症每年就影响约4000万人，保守估计每年的总经济负担至少为1250亿美元。两种适应症的现有药物疗法不是一致有效的，并且经常具有不期望的副作用。这些局限性表明，通过CNS中的加压素受体拮抗作用的新治疗方法可能为改善结局提供重要机会。在这篇综述中，考虑了自2005年以来该类化合物的发展。介绍了最近专利中描述的最先进的临床候选药物和较新的化合物。
A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. The scientific bases for vasopressin antagonists as a pharmacotherapy for anxiety and depression include: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression, 2) recognition that AVP, not corticotrophin releasing factor (CRF), drives HPA function associated with chronic psychological stress, 3) the CNS localization of vasopressin V1a and V1b receptors in limbic system regions involved in HPA regulation and control of social behaviors, and 4) preclinical data showing efficacy in animal models employed as screens for anxiolytic and antidepressant activity. The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. In the United States alone, anxiety and depression affect some 40 million people each year and carry a conservatively estimated annual total economic burden of at least $125 billion. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through vasopressin receptor antagonism in the CNS may offer significant opportunities for improved outcomes. In this review, the development of compounds in this class since 2005 is considered. The most advanced clinical candidates and newer compounds described in recent patents are presented.