Design of more potent antagonists of the antidiuretic responses to arginine-vasopressin

Abstract

As part of a program aimed at designing more potent and selective antagonists of the antidiuretic responses to arginine-vasopressin (AVP), O-alkyl-D-tyrosine (where alkyl = methyl, ethyl, isopropyl, or n-propyl) at position 2 in the 8 previously reported O-alkyl-L-tyrosine antagonists of antidiuretic and vasopressor responses was substituted to AVP. D-tyrosine was substituted for L-tyrosine in 2 vasopressor antagonists with weak antidiuretic agonistic activity, [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),4-valine,8-D-arginine]vasopressin [d(CH2)5VDAVP] and its L-arginine isomer .delta.(CH2)5VAVP]. The 10 analogs, synthesized by the solid-phase method, are as follows: 1, d(CH2)5-D-Tyr(Me)VDAVP; 2, d(CH2)5-D-Tyr(Et)VDAVP, 3, d(CH2)5-D-Tyr(i-Pr)VDAVP; 4, d(CH2)5-D-Tyr(n-Pr)VDAVP; 5, d(CH2)5-D-Tyr(Me)VAVP; 6, d(CH2)5-D-Tyr(Et)VAVP; 7, d(CH2)5-D-Tyr(n-Pr)VAVP; 8, d-(CH2)5-D-Tyr(i-Pr)VAVP; 9, d(CH2)5-D-TyrVDAVP; 10, d(CH2)5-D-TyrVAVP. These analogs were tested for agonistic and antagonistic activities in rat antidiuretic and rat vasopressor systems. All 10 D-tyrosine analogs possess transient weak antidiuretic activities (0.004-0.05 U/mg). Subsequent doses of AVP are reversibly antagonized for 1-3 h, depending on the dose of the antagonist. They exhibit the following antiantidiuretic pA2 values: 1, 7.19 .+-. 0.11; 2, 7.59 .+-. 0.04; 3, 7.51 .+-. 0.06; 4, 7.60 .+-. 0.05; 5, 7.77 .+-. 0.07; 6, 7.81 .+-. 0.07, 7, 7.66 .+-. 0.11; 8, 7.61 .+-. 0.06; 9, 7.03 .+-. 0.05; 10, 7.51 .+-. 0.08. They are all effective antagonists of vasopressor responses to AVP. Analogs 1-8 are 2-10 times more potent than their respective O-alkyl-L-tyrosine isomers as antidiuretic antagonists. Since the vasopressor potencies of the O-alkyl-L-tyrosine analogs have either diminished or remained virtually unchanged, these analogs exhibit a selective increase in their antiantidiuretic/antivasopressor ratios with respect to their respective O-alkyl-L-tyrosine analogs. The finding that the substitution of an unalkylated D-tyrosine for L-tyrosine in d(CH2)5VDAVP and d(CH2)5VAVP converts these weak antidiuretic agonists into potent antagonists of antidiuretic responses to AVP is highly significant, especially in view of the relative ease of synthesis and much higher yields of unalkylated vs. alkylated tyrosine analogs. These 10 new analogs are potentially useful as pharmacological tools and as therapeutic agents. The findings presented here have also obvious potential for the design of even more potent and selective antidiuretic antagonists.