The D136A mutation of the V2 vasopressin receptor induces a constitutive activity which permits discrimination between antagonists with partial agonist and inverse agonist activities

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 Vt 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 tao cyclic peptides d(CH2)(5)[D-Tyr(Et)(2),- Val(4),Tyr-NH29]AVP and d(CH2)(5)[D-Ile(2),He-4,Tyr-NH29]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, (C) 1998 Federation of European Biochemical Societies.