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Abstract

Neurohypophyseal hormone analogues containing sarcosine (Sar) in position 7 were prepared to design more potent and selective oxytocin antagonists. The three analogues (1-3) of [Sar⁷]arginine-vasopressin ([Sar⁷]AVP) and six analogues (4-9) of [Sar⁷]arginine-vasotocin ([Sar⁷]AVT) had a reduced affinity for antidiuretic V₂ receptors. The [Sar⁷]AVP derivatives (1-3) were potent antiuterotonic (in vitro pA₂ = 7.5-8.4, in vivo 6.6-7.1) and antipressor (pA₂ = 7.2-8.0) agents. The [Sar⁷]AVT analogues (4-9) were more potent and selective uterotonic antagonists (in vitro pA₂ = 7.9-8.6, in vivo 7.1-7.5); their antipressor potencies were reduced (pA₂ = 6.4-7.7). The change of the antagonistic potencies was paralleled by a change in the receptor affinities. Among other antiuterotonic analogues, [Mca¹, D-Phe², Sar⁷]AVT (4, Mca = beta-mercapto- beta,beta-cyclopentamethyl-enepropionic acid) and [Mca¹, D-Tyr(OEt)²,Sar⁷]AVT (6) were synthesized, two highly potent antiuterotonic compounds (in vitro pA₂ = 8.3, in vivo 7.4 and 7.5, respectively) with reduced antipressor activity (pA₂ = 6.4) and reduced binding affinity to V₂ receptors (K_d = 421 and 35 nM, respectively) and no anti-antidiuretic effect. Another potent antiuterotonic analogue, [Mca¹,D-Trp²,-Sar⁷]AVT (9, in vitro pA₂capability to V₂ receptors (K_d approximately 0.3 mM). These analogues should lead to the design of even more potent and selective oxytocin antagonists.