Synthetic antagonists of in vivo antidiuretic and vasopressor responses to arginine-vasopressin

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Abstract
Four analogs of [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),4-valine,8-D-arginine]vasopressin [d-(CH2)5 VDAVP] and 4 analogs of its L-arginine isomer d(CH2)5 VAVP with O-methyl-, O-ethyl-, O-isopropyl and O-n-propyltyrosine substituents at position 2 were prepared by the solid-phase method using a slightly modified reoxidation procedure following deblocking with sodium in liquid ammonia to overcome losses due to insolubility. These analogs are the following: 1, d(CH2)5Tyr(ME)VDAVP; 2, d(CH2)5Tyr(Et)VDAVP; 3, d(CH2)5Tyr(i-Pr)VDAVP; 4 d(CH2)5Tyr(n-Pr)VDAVP; 5, d(CH2)5Tyr(Me)VAVP; 6 d(CH2)5Tyr(Et)VAVP; 7, d(CH2)5Tyr(i-Pr)VAVP; 8, d(CH2)5Tyr(n-Pr)VAVP. These analogs were tested for agonistic and antagonistic activities in rat antidiuretic and rat vasopressor assay systems. All 8 analogs cause a transient antidiuresis when injected i.v. and effectively antagonize antidiuretic responses to subsequent injections of arginine-vasopressin (AVP). They exhibit the following antiantidiuretic pA2 [competitive antagonistic activity] values: 1, 6.68 .+-. 0.11; 2, 7.10 .+-. 0.08; 3, 6.88 .+-. 0.07; 4, 6.67 .+-. 0.05; 5, 7.35 .+-. 0.06; 6, 7.57 .+-. 0.06; 7, 7.32 .+-. 0.10; 8, 7.29 .+-. 0.07. They are effective antagonists of vasopressor responses to AVP, with antivasopressor pA2 values in the range of 7.86-8.44. This series O-ethyl substitution on the Tyr at position 2 is optimal for antiantidiuretic potency and L-Arg is far superior to D-Arg in this regard. Analog 6 with an antiantidiuretic pA2 of 7.57 .+-. 0.06 is the most potent of the 8 antidiuretic antagonists. These are the 1st known effective antagonists of in vivo antidiuretic responses to AVP. They are potentially useful pharmacological tools for studies on the roles of AVP in regulating water balance in normal and pathophysiological states in animals and in humans. They also serve as excellent lead compounds for the design of even more potent antagonists for potential therapeutic use for the treatment of hyponatremia secondary to inappropriate secretion of the antidiuretic hormone (the Schwartz-Bartter syndrome).

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