[1-Deaminopenicillamine,4-threonine]oxytocin, a potent inhibitor of oxytocin

Abstract

[1-Deaminopenicillamine,4-threonine]oxytocin was prepared in duplicate from S-benzyl-3-mercapto-3,3-dimethylpropanoyl-Tyr(Bzl)-Ile-Thr(Bzl)-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 (I) by removal of the Bzl-protecting groups with Na-NH3, followed by cyclization of the resulting disulfhydryl compound with K3Fo(CN)6. The analogue was purified by desalting on Sephadex G-15 in 50% acetic acid and gel filtration of Sephadex G-15. The protected peptide I was synthesized (a) by the solid-phase method and (b) by a combination of solid-phase synthesis and an [8 + 1] coupling in solution. The analogue has no detectable agonist activity in rat vasopressor or isolated rat uterus assays. It has an antivasopressor pA2 of 6.67 +/- 0.09. It is a potent inhibitor of the in vitro oxytocic response to oxytocin and has a pA2 value of 7.46 +/- 0.04. (Material from the repeat synthesis has a pA2 value of 7.59 +/- 0.08.) Thus the substitution of threonine for glutamine in the antagonist [1-deaminopenicilliamine]oxytocin (pA2, 7.14 +/- 0.05) has effected a twofold increase in inhibitory potency. [1-deaminopenicillamine,4-threonine]oxytocin is one of the most potent inhibitors of oxytocin known to date.

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

“…Of the many OT antagonists (peptide and non-peptide) reported to date, only one, atosiban, has been approved (in Europe) under the Tradename Tractocile for the treatment of preterm labor [70]. This peptide OT antagonist, d[D-Tyr(Et) 2 , Thr 4 ]OVT, first reported in 1986 [26], was based on earlier lead peptide OT antagonists from this and other laboratories [11][12][13][14][15][16][17][18][19][20][21][22]. After many years of extensive clinical trials, atosiban is being widely used as the therapy of choice for preterm labor [3,5,6,[70][71][72][73].…”

“…Thus there is a pressing need for OT antagonists with superior potency, and selectivity than atosiban. As part of a longstanding program aimed at the design and synthesis of potent and selective OT antagonists [17][18][19][20][21][22]29,30,[46][47][48][54][55][56], a series of OT antagonists was reported that is more potent and selective than atosiban in in vivo assays in the rat [47]. These were designed by replacing the Tyr(Me) residue at position 2 in one of our early, somewhat selective OT antagonists: desGly-NH 2 , d(CH 2 ) 5 [Tyr(Me) 2 , Thr 4 ]OVT (A) [30] with D-Tyr(Me), D-Tyr, D-Phe and D-Trp.…”

The Design of Effectivein VivoAntagonists of Rat Uterus and Milk Ejection Responses to Oxytocin*

“…Substitution of threonine in the 4-position has been found to enhance the antagonistic activity of dPOT, as measured on the rat uterus in the absence of Mg ++ (7). This substitution also enhances antagonistic activity and reduces agonistic activity of dPOT in the presence of Mg ++ or in vivo ( Table 2), but the resulting analog, dPTOT, did not antagonize the milk ejection response.…”

Structural studies with weak oxytocin antagonists

“…The results of the pharmacological testing of these analogues, regardless of the minor structural changes of the tocin ring, thus suggest a conformation unfavorable for optimal interaction with the receptor, or, in other words, oxytocin antagonists may bind to oxytocin receptors quite differently. It is well known [17,18] (Table 1). To further examine, along this line, the effect of the side chain of the Tyr 2 residue, the analogue [Phe2,Thr(OMe) 5, OrnS]OT was synthesized and tested ( Table 1).…”