Synthesis and some pharmacological properties of 18 potent O-alkyltyrosine-substituted antagonists of the vasopressor responses to arginine-vasopressin

Using the Merrifield solid-phase method, we have synthesized 18 new 2-O-alkyltyrosine-substituted analogues (where alkyl = methyl and ethyl) of the arginine-vasopressin (AVP) vasopressor antagonists [1-deaminopenicillamine]-arginine-vasopressin (dPAVP), [1-(beta-mercapto-beta,beta-diethylpropionic acid)]arginine-vasopressin (dEt2AVP), and [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)]arginine-vasopressin (d(CH2)5AVP) and of their 8-D-arginine (d(R2)DAVP) analogues, their 4-valine (dR2VAVP) analogues, and their 4-valine,8-D-arginine (d(R2)VDAVP) analogues [where R = CH3 or C2H5 and 2R = (CH2)5]. These analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor and rat antidiuretic and in vitro rat uterus assay systems. Although many exhibit very low antidiuretic activities, none of the new analogues antagonize antidiuretic responses to AVP. They exhibit no evident pressor activities and are in fact all highly effective antagonists of the vasopressor responses to AVP. They are also potent antagonists of the in vitro oxytocic responses to oxytocin, both in the absence and in the presence of Mg2+. These analogues together with their corresponding antivasopressor pA2 values are as follows: 1. dPTyr(Et)AVP, 8.40 +/- 0.08; 2. dEt2Tyr(Me)AVP, 8.53 +/- 0.06; 3. dEt2Tyr(Et)AVP, 8.46 +/- 0.08; 4. d(CH2)5Tyr(Et)AVP, 8.47 +/- 0.04; 5. dPTyr(Me)DAVP, 8.31 +/- 0.08; 6. dPTyr(Et)DAVP, 8.27 +/- 0.06; 7. dEt2Tyr(Me)DAVP, 8.57 +/- 0.03; 8. dEt2Tyr(Et)DAVP, 8.33 +/- 0.06; 9. d(CH2)5Tyr(Me)DAVP, 8.41 +/- 0.05; 10. d(CH2)5Tyr(Et)DAVP, 8.45 +/- 0.05; 11. dPTyr(Me)VAVP, 8.36 +/- 0.07; 12. dPTyr(Et)VAVP, 8.07 +/- 0.13; 13. dEt2Tyr(Me)VAVP, 8.29 +/- 0.08; 14. dEt2Tyr(Et)VAVP, 8.42 +/- 0.06; 15. dPTyr(Me)VDAVP, 7.84 +/- 0.06; 16. dPTyr(Et)VDAVP, 8.46 +/- 0.03; 17. dET2Tyr(Me)VDAVP, 8.35 +/- 0.10; 18. dEt2Tyr (Et)VDAVP, 8.19 +/- 0.07. Seven of these analogues are clearly more potent vasopressor antagonists than their respective unalkylated tyrosine-containing parents. In the remaining 11, antagonistic potency was not changed significantly. In no instance did 2-O-alkyltyrosine substitution decrease antagonistic potency. With pA2 values equal to or greater than 8.40, nine of these antagonists (numbers 1-4, 7, 9, 10, 14, and 16) are among the most potent vasopressor antagonists reported to date. They could thus serve as additional valuable pharmacological tools in studies on the roles of AVP in the control of blood pressure in normal and in pathophysiological conditions. These findings may also provide useful clues to the design of more potent and selective antagonists of AVP.