ENHANCED SELECTIVITY OF OXYTOCIN ANTAGONISTS CONTAINING SARCOSINE IN POSITION-7

Neurohypophyseal hormone analogues containing sai cosine (Sar) in posi tion 7 were prepared to design more potent and selective oxytocin anta gonists. The three analogues (1-3) of [Sar(7)] arginine-vasopressin ([ Sar(7)]AVP) and six analogues (4-9),of [Sar(7)]arginine-vasotocin ([Sa r(7)]AVT) had a reduced affinity for antidiuretic V-2 receptors. The [ Sar(7)]AVP derivatives (1-3) were potent antiuterotonic (in vitro pA(2 ) = 7.5-8.4, in vivo 6.6-7.1) and antipressor (pA(2) = 7.2-8.0) agents . The [Sar(7)]AVT analogues (4-9) were more-potent and selective utero tonic antagonists (in vitro pA(2) 7.9-8.6, in vivo 7.1-7.5); their ant ipressor potencies were reduced (pA(2) = 6.4-7.7). The change of the a ntagonistic potencies was paralleled by a change in the receptor affin ities. Among other antiuterotonic analogues, [Mca(1),D-Phe(2),Sar(7)]A VT (4, Mca = ta-mercapto-beta,beta-cyclopentamethylenepropionic acid) and [Mca(1), D-Tyr(OEt)(2),Sar(7)]AVT (6) were synthesized, two highly potent antiuterotonic compounds (in vitro pA(2) 8.3, in vivo 7.4 and 7.5, respectively) with reduced antipressor activity (pA(2) = 6.4) and reduced binding affinity to V-2 receptors (K-d = 421 and 35 nM, respe ctively) and no anti-antidiuretic effect. Another potent antiuterotoni c analogue, [Mca(1),D-Trp(2),Sar(7)]AVT (9, in vitro pka = 7.9, in viv e 7.5) has virtually no binding capability to V-2 receptors (K-d simil ar to 0.3 mM). These analogues should lead to the design of even more potent and selective oxytocin antagonists.