Synthetic antagonists of in vivo responses by the rat uterus to oxytocin

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Abstract
As part of a program to synthesize in vivo antagonists of oxytocin, the following 4 analogs were synthesized and tested for antagonistic activities in rat uterus and rat vasopressor assay systems: [1-(.beta.-mercapto-.beta.,.beta.-diethylpropionic acid),4-threonine]oxytocin (1, dEt2TOT), [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid),4-threonine]oxytocin [2,d(CH2)5TOT], [1-deaminopenicillamine,2-O-methyltyrosine]oxytocin [3,dPTyr(Me)OT], and [1-deaminopenicillamine,2-O-methyltyrosine,4-threonine]oxytocin [4, dPTyr(Me)TOT]. The required protected intermediates were synthesized by a combination of solid-phase peptide synthesis and by individual 8 + 1 couplings in solution. All 4 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 [negative log of the molar concentration of a competitive antagonist that reduces the response to 2 x units of agonist to equal the response to x units in the absence of antagonist] values in each of the assay systems a-c: (1) (a) 7.72 .+-. 0.11, (b) 7.36 .+-. 0.09, (c) 6.47 .+-. 0.11; (2) (a) 7.91 .+-. 0.13, (b) 7.81 .+-. 0.09, (c) 6.94 .+-. 0.11; (3) (a) 7.76 .+-. 0.12 (b) 7.80 .+-. 0.12, (c) 6.86 .+-. 0.12 (4) (a) 7.64 .+-. 0.14, (b) 7.79 .+-. 0.09, (c) 6.84 .+-. 0.10. They have the following antivasopressor pA2 values: (1) 6.30 .+-. 0.13; (2) 5.86 .+-. 0.03; (3) 7.59 .+-. 0.05; (4) 7.32 .+-. 0.04. Compounds 2-4 are among the most potent in vivo antagonists of oxytocin reported to date.