Vasopressin receptor antagonists (vaptans) are a new class of drugs to treat congestive heart failure. Since there are three subtypes of the receptor located in different tissues, it is important to devise tailor-made vaptans to target the appropriate receptor subtype. The binding of three vaptans, OPC21268, mozavaptan and tolvapatan was measured to the human V1-vascular vasopressin receptor (hV1R). Whereas arginine vasopressin (AVP) binds to hV1R and hV2R with equal affinity, vaptans interact differently with the receptor subtypes. The interaction of the three vaptans to the hV1R was probed by binding experiments to point mutants of residues postulated to line the binding pocket. The measurements suggest that the binding pocket on the hV1R is too small for tight binding of tolvaptan. The somewhat smaller mozavaptan is a slightly better binder to the hV1R. The data suggest ways to increase the affinity of tolvaptan to the hV1R by chemical modification.
Keywords: Antagonist, GPCR, Receptor, Mozavaptan, Tolvaptan, Vaptan, Vasopressin, arginine vasopressin (AVP), hV1R, vasodilation, hyponatremia, hypervolemia, V2R, adenylyl cyclase