Development and therapeutic indications of orally-active non-peptide vasopressin receptor antagonists

Vasopressin (AVP) is a cyclic nonapeptide hormone that exhibits many physio logical effects including free water reabsorption. vasoconstriction, cellul ar proliferation and adrenocorticotrophic hormone (ACTH) secretion. In a he althy organism. AVP plays an important role in the homeostasis of fluid osm olality 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. dysme norrhoea rind ocular hypertension, AVP may play an important role in their pathophysiology. Recently, orally-active non-peptide AVP receptor antagonis ts 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 bee n studied extensively, while others are currently under investigation. Pote ntial therapeutic indications for AVP receptor antagonists comprise: The blockade of V1-vascular AVP receptors in arterial hypertension, congest ive heart failure, Raynaud's syndrome, peripheral vascular disease and dysm enorrhoea. The blockade of V-2-renal AVP receptors in the syndrome of inappropriate se cretion of vasopressin, congestive heart failure, liver cirrhosis, nephroti c syndrome and any state of excessive retention of free water and subsequen t dilutional hyponatraemia. The blockade of V-3-pituitary AVP receptors in ACTH-secreting tumours. This review examines the pharmacology of orally-active non-peptide AVP rece ptor antagonists and their clinical applications.