PT  - JOURNAL ARTICLE
AU  - DANIEL BUTLEN
AU  - GILLES GUILLON
AU  - RABARY M. RAJERISON
AU  - SERGE JARD
AU  - WILBUR H. SAWYER
AU  - MAURICE MANNING
TI  - Structural Requirements for Activation of Vasopressin-sensitive Adenylate Cyclase, Hormone Binding, and Antidiuretic Actions: Effects of Highly Potent Analogues and Competitive Inhibitors
DP  - 1978 Nov 01
TA  - Molecular Pharmacology
PG  - 1006--1017
VI  - 14
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/14/6/1006.short
4100  - http://molpharm.aspetjournals.org/content/14/6/1006.full
SO  - Mol Pharmacol1978 Nov 01; 14
AB  - Membranes prepared from the medullopapillary portion of pig and rat kidneys were used to test the relative abilities of 11 arginine-vasopressin structural analogues to activate adenylate cyclase and to inhibit [3H]lysine-vasopressin binding to these membrane preparations. The analogues tested were: [1-deaminopenicillamine, 2-O-methyltyrosine]-arginine-vasopressin; [1-deaminopenicillamine]arginine-vasopressin; [1-deaminopenicillamine, 4 valine, 8-D-arginine]-vasopressin (dP-V-DAVP); [8-D-arginine]-vasopressin; [2-O-methyltyrosine]arginine-vasopressin; [4-valine, 8-D-arginine]-vasopressin; [4-valine]arginine-vasopressin; deamino [4-threonine, 8-D-arginine]-vasopressin; deamino [8-D-arginine]-vasopressin; deamino [4-valine, 8-D-arginine]-vasopressin; [1(β-mercapto-β,β-cyclopentamethylene propionic acid), 4-valine, 8-D-arginine]-vasopressin (cyclo-dV-DAVP). Cyclo-dV-DAVP behaved like a competitive inhibitor of vasopressin-induced adenylate cyclase activation. The apparent Ki values were 10 and 310 nM for the rat and pig systems, respectively. This peptide is the most active antagonist described so far. dP-V-DAVP behaved like a competitive inhibitor on the pig system (Ki = 2.9 µM) and was found to produce a maximal enzyme activation that was 75% of that induced by arginine-vasopressin in the rat system (Kact = 3.7 nM). In both the rat and pig systems there was a good correlation between the Kbind values for binding to renal membranes and the corresponding Kact or Ki values for the adenylate cyclase response. The structural requirements for binding to the pig renal receptor and to the rat renal receptor were found to be different. When one takes into account for metabolic stability of the ADH analogues tested (as estimated by the relative duration of the antidiuretic response), there was a satisfactory correlation between the antidiuretic activities of the peptides tested in the rat and their abilities to activate the adenylate cyclase present on renal membranes.