The D136A mutation of the V 2 vasopressin receptor induces a constitutive activity which permits discrimination between antagonists with partial agonist and inverse agonist activities

Abstract

The substitution, in the human V 2 vasopressin receptor, of the aspartate at position 136 by alanine leads to agonist-independent activation of this mutant V 2 receptor. Pharmacological studies of the D136A V 2 receptor helped us in characterizing different V 2 receptor antagonists. SR-121463A and OPC-31260, two non-peptide antagonists, behaved as inverse agonists, while two cyclic peptides d(CH 2) 5[ d-Tyr(Et) 2,Val 4,Tyr-NH 2 9]AVP and d(CH 2) 5[ d-Ile 2,Ile 4,Tyr-NH 2 9]AVP known to be V 2 antagonists, demonstrated clear partial agonist properties. The finding of a constitutively activated human V 2 receptor represents a useful tool in characterizing V 2 receptor antagonist ligands.