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

Vasopressin (AVP) and oxytocin (OT) are cyclic nonapeptides whose actions are mediated by the stimulation of specific G-protein-coupled receptors (GPCRs) currently classified into V(1)-vascular (V(1)R), V(2)-renal (V(2)R) and V(3)-pituitary (V(3)R) AVP receptors and OT receptors (OTR). The signal transduction pathways coupled to the different subtypes of AVP/OT receptors are reviewed. The recent cloning of the different members of the AVP/OT family of receptors now allows the extensive characterisation of the molecular determinants involved in agonist and antagonist binding, as well as signal transduction coupling. Potential therapeutic uses of AVP receptor antagonists include: the blockade of V(1)-vascular AVP receptors in arterial hypertension, congestive heart failure (CHF) and peripheral vascular diseases; the blockade of V(2)-renal AVP receptors in the syndrome of inappropriate vasopressin secretion, CHF, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent hyponatraemia; the blockade of V(3)-pituitary AVP receptors in adrenocorticotropin (ACTH)-secreting tumours. The pharmacological and clinical profile of orally-active non-peptide AVP receptor antagonists is reviewed.