Design & Synthesis of Novel CNS-Active Oxytocin and Vasopressin Receptor Ligands

描述（由申请人提供）：抗利尿激素和催产素调节许多重要的哺乳动物功能。后叶加压素肽的活性包括通过刺激肾脏内的后叶加压素2受体亚型来调节尿浓度，通过激活血管内的后叶加压素1a受体来调节血压，以及通过激活垂体后叶加压素1b受体来调节ACTH。催产素肽在子宫和乳腺中分别负责分娩和泌乳控制。抗利尿激素和催产素的受体也存在于中枢神经系统（CNS）中。缺乏中枢神经系统可及和亚型选择性配体阻碍了神经系统疾病领域的进展。抗利尿激素和催产素是在动物社会行为模型中具有深远影响的关键因素。这些模型正被用于更全面地了解人类社会缺陷障碍，例如广泛性发育障碍（PDD）的症状以及压力对妇女的影响。开发小分子类药物激动剂用于催产素和抗利尿激素1a受体（OTR和V1aR），这些激动剂具有选择性，能够穿透大脑，并在行为模型中进行测试，将大大促进我们的理解。我们的目标是确定经过验证的先导化合物，以便进一步开发。公共卫生相关性：该项目有潜力确定第一批设计的药物，用于治疗广泛性发育障碍的症状，如自闭症和自闭症谱系疾病，以及识别和治疗涉及神经调节剂催产素和/或抗利尿激素的其他疾病。

DESCRIPTION (provided by applicant): The cyclic nonapeptides hormones vasopressin and oxytocin regulate many important mammalian functions. Vasopressin peptide activities include regulation of urine concentration by the stimulation of vasopressin 2 receptor subtypes in the kidneys, regulation of blood pressure by activation of vasopressin 1a receptors in the vasculature, and ACTH modulation by activation of pituitary vasopressin 1b receptors. Oxytocin peptide is responsible for labor and lactation control in the uterus and mammary glands respectively. Receptors for vasopressin and oxytocin are, however also to be found in the central nervous system (CNS). The lack of CNS accessible and subtype-selective ligands has hindered progress in the area of neurological disorders. Vasopressin and oxytocin are key factors that have been shown to have profound effects in animal models of social behavior. These models are being used to understand more fully, human social deficit disorders such as the symptoms seen in the pervasive development disorders (PDD) and the effects of stress on women. The development small molecule, drug-like agonists for the oxytocin and vasopressin 1a receptors (OTR and V1aR) that are selective and able to penetrate the brain and to test them in models of behavior will significantly advance progress in our understanding. Our goal will be to identify validated lead compounds for further development. PUBLIC HEALTH RELEVANCE: This program has the potential to identify the first designed medicines for the treatment of symptoms of the pervasive development disorders such as autism and the autistic spectrum of diseases as well as the identification and treatment of other disorders where the neuromodulators oxytocin and/or vasopressin are implicated.