[1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine-vasopressin and [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)]arginine-vasopressin, two highly potent antagonists of the vasopressor response to arginine-vasopressin

Abstract

As part of a study on the design and synthesis of antagonists of the vasopressor response to arginine-vasopressin (AVP), [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine-vasopressin [1, d(CH2)5Tyr(Me)AVP] (in duplicate) and [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)]arginine-vasopressin [2, d(CH2)5AVP] were synthesized. The required protected intermediate for 1 was synthesized by a combination of solid-phase synthesis and an 8 + 1 coupling in solution and entirely by solid-phase synthesis. The required protected precursor for 2 was synthesized entirely by solid-phase methods. Both 1 and 2 were tested for agonistic and antagonistic activities in rat vasopressor, rat antidiuretic and rat uterus assay systems. d(CH2)5Tyr(Me)AVP exhibits a surprisingly potent and prolonged antivasopressor effect. It has an antivasopressor pA2 [effective concentration of agonist to antagonist] of 8.62 .+-. 0.03 and an antidiuretic potency of 0.31 .+-. 0.07 unit/mg. Material from the 2nd synthesis of d(CH2)5Tyr(Me)AVP has a pA2 value of 8.67 .+-. 0.02. d(CH2)5AVP exhibited a potent, but less prolonged, antivasopressor effect. It has an antivasopressor pA2 of 8.35 .+-. 0.09 and an antidiuretic potency of only 0.033 .+-. 0.005 unit/mg. These are the 2 most potent vasopressor antagonists reported to date. Both analogs antagonize the actions of oxytocin on the rat uterus (a) in the absence of Mg2+, (b) in the presence of 0.5 mM Mg2+ and (c) in situ. They exhibit, respectively, the following pA2 values in each of the assay systems a-c: (1) a, 8.13 .+-. 0.12; b, 7.24 .+-. 0.07; c, 6.62 .+-. 0.07; (2) a, 8.15 .+-. 0.20; b, 7.19 .+-. 0.08; c, 6.79 .+-. 0.19. With their potent ability to antagonize the vasopressor effects of AVP, d(CH2)5Tyr(Me)AVP and d(CH2)5AVP should be valuable additions to previously reported antagonists for use as pharmacological tools with which to probe the possible role(s) of AVP in cardiovascular regulation in normal and pathophysicological states.