DESIGN AND SYNTHESIS OF POTENTIN VIVOANTAGONISTS OF OXYTOCIN

Abstract

We have previously shown that the substitution of 8‐ornithine and 2‐O‐methyltyrosine alone and in combination in [1‐deaminopenicillamine] oxytocin (dPOT) brought about enhancements in antagonistic potencies to responses to oxytocinin vivo. To explore the effects of these subtitutions in analogs of dPOT containing larger alkyl substitutents on the β carbon at position 1 and on the tyrosine residue at position two, the following six analogs were synthesized: [1‐(β‐mercapto‐β, β‐diethylpropionic acid), 8‐ornithine] vasotocin (1, dEt2OVT); [1‐β‐mercapto‐β, β‐cyclopentamethylenepropionic acid), 8‐ornithine] vasotocin [2, d(CH2)5OVT); [1‐β‐mercapto‐β, β‐diethylpropionic acid), 2‐O‐methyltyrosine, 8‐ornithine]vasotocin [3, dEt2Tyr(Me)OVT]; [1‐(β‐mercapto‐β, β‐diethylpropionic acid), 2‐O‐ethyltyrosine, 8‐ornithine] vasotocin [4, dEt2Tyr(Et)OVT]; [1‐β‐mercapto‐β', β‐cyclopentamethylenepropionic acid), 2‐O‐methyltyrosine, 8‐ornithine] vasotocin [5, d(CH2)5Tyr(Me)OVT]; [1‐β‐mercapto‐β, β‐cyclopentamethylenepropionic acid), 2‐O‐methyltyrosine, 8‐ornithine] vasotocin [6, d(CH2)5Tyr(Et)OVT].The required protected intermediates were synthesized by a combination of solid‐phase synthesis and by individual 8 + 1 couplings in solution. All six analogs antagonize the actions of oxytocin on the rat uterus in the absence of Mg2+, in the presence of 0.5 mM Mg2+and in situ. They also antagonize milk ejection responses to oxytocin, and the vasopressor responses to arginine vasopressin, and all have very low antidiuretic activities. With pA2values of 7.35 ± 0.08 and 7.37 ± 0.17, respectively, compounds 3 and 5 are the two most potent in vivo antagonists of oxytocin reported to date.