Characterization of a novel and selective V1B receptor antagonist.
It has been argued that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a major biological abnormality in patients suffering from psychiatric conditions such as major depression. Both arginine vasopressin (AVP) and corticotrophin releasing factor (CRF) are responsible for stimulating the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. CRF is thought to be the predominant secretagogue under normal conditions but AVP may play a more important role in situations of aberrant/chronic stress. Studies in patients suffering from melancholic depression indicate a hyper-responsiveness to agonism at the vasopressin receptor type 1B (V(1B)); patients display a heightened ACTH release after challenge with the mixed V(1B)/V(2) (vasopressin receptor type 2) agonist desmopressin in comparison to control subjects. A V(1B) antagonist has been developed which has significant selectivity for the human V(1B) receptor over the other members of the vasopressin receptor sub-family. The compound acts as an effective antagonist at both the human recombinant receptor (stably expressed in Chinese hamster ovary (CHO) cells) and the native rat V(1B) receptor (using isolated anterior pituitary cells), blocking the induction of luciferase and the release of ACTH, respectively. In vivo the compound can block the release of ACTH after challenge with a variety of V(1B) agonists. It can also attenuate the ACTH response to acute stressors in rats. Interestingly, this compound does not modulate the activity of the HPA axis under normal basal conditions.
Craighead
Mark
M
Department of Molecular Pharmacology, Organon Laboratories (a part of the Schering-Plough Corporation), Newhouse, UK.
Milne
Rachel
R
Campbell-Wan
Leigh
L
Watson
Lynn
L
Presland
Jeremy
J
Thomson
Fiona J
FJ
Marston
Hugh M
HM
Macsweeney
Clíona P
CP
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000502:physiology / Q000627:therapeutic use; D016466:CHO Cells; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D019964:Mood Disorders / Q000188:drug therapy*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000503:physiopathology; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000187:drug effects / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
D000324:Adrenocorticotropic Hormone; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone; D003894:Deamino Arginine Vasopressin; D017483:Receptors, Vasopressin; D017367:Selective Serotonin Reuptake Inhibitors