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

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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.