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

The substitution, in the human V-2 vasopressin receptor, of the aspartate a t position 136 by alanine leads to agonist-independent activation of this m utant Vt receptor. Pharmacological studies of the D136A V-2 receptor helped us in characterizing different V-2 receptor antagonists, SR-121463A and OP C-31260, two non-peptide antagonists, behaved as inverse agonists, while ta o 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 clea r partial agonist properties. The finding of a constitutively activated hum an V-2 receptor represents a useful tool in characterizing V-2 receptor ant agonist ligands, (C) 1998 Federation of European Biochemical Societies.