Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists.
Vasopressin (AVP) is a cyclic nonapeptide hormone that exhibits many physiological effects including free water reabsorption, vasoconstriction, cellular proliferation and adrenocorticotrophic hormone (ACTH) secretion. In a healthy organism, AVP plays an important role in the homeostasis of fluid osmolality and volume status. However, in several diseases or conditions such as the syndrome of inappropriate secretion of AVP (SIADH), congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhoea and ocular hypertension, AVP may play an important role in their pathophysiology. Recently, orally-active non-peptide AVP receptor antagonists were developed by random screening of chemical entities and optimisation of lead compounds. These include agents specific for the V(1)-vascular and V(2)-renal AVP receptor subtypes. Dual V(1)/V(2) AVP receptor antagonists are also being studied. Some of these non-peptide receptor antagonists have been studied extensively, while others are currently under investigation. Potential therapeutic indications for AVP receptor antagonists comprise: 1) The blockade of V(1)-vascular AVP receptors in arterial hypertension, congestive heart failure, Raynaud's syndrome, peripheral vascular disease and dysmenorrhea. 2) The blockade of V(2)-renal AVP receptors in the syndrome of inappropriate secretion of vasopressin, congestive hart failure, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent dilutional hyponatraemia. 3) The blockade of V(3)-pituitary AVP receptors in ACTH-secreting tumours. This review examines the pharmacology of orally-active non-peptide AVP receptor antagonists and their clinical applications.
Paranjape
S B
SB
Case Western Reserve University School of Medicine and University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, Ohio 44106-4951, USA.
Thibonnier
M
M
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003919:Diabetes Insipidus / Q000188:drug therapy; D004412:Dysmenorrhea / Q000188:drug therapy; D005260:Female; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007010:Hyponatremia / Q000188:drug therapy
D065092:Antidiuretic Hormone Receptor Antagonists