Enhanced selectivity of oxytocin antagonists containing sarcosine in position 7

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 (Kd = 421 and 35 nM, respectively) and no anti-antidiuretic effect. Another potent antiuterotonic analogue, [Mca1,D-Trp2,-Sar7]AVT (9, in vitro pA2 = 7.9, in vivo 7.5) has virtually no binding capability to V2 receptors (Kd approximately 0.3 mM). These analogues should lead to the design of even more potent and selective oxytocin antagonists.