Synthesis of [1-sarcosine,8-O-methylserine]angiotensin II and 1-substituted analogs of [8-threonine]angiotensin II as antagonists of angiotensin II

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Abstract
[1-N-methylisoleucine,8-threonine]- (I), [1-dimethylglycine,8-threonine]- (II), [1-guanidineacetic acid,8-threonine]- (III), des-1-aspartic acid-[8-threonine]- (IV), and [1-sarcosine,8-O-methylserine]angiotensin II (VI) were synthesized by Merrifield''s solid-phase procedure to study the effect of substituents in position 1 on the antagonistic activity of [1-sarcosine,8-threonine]angiotensin II, and a change in size and branching in position 8 of [1-sarcosine,8-O-methylthreonine]angiotensin II. The analogues I-V caused an initial rise in blood pressure (30 min of infusion, 250 ng/kg per min in vagotomized ganglion-blocked rats) of 8.05, 11.7, 3.50, 4.5 and 11.16 mmHg. The pA2 [inhibition of contractile activity of angiotension II] values (rabbit aortic strips) obtained were 7.68, 7.53, 7.23, 7.53 and 9.66, and the dose ratios (in vagotomized ganglion-blocked rats infused at 250 ng/kg per min) obtained were 2.37, 4.49, 1.02, 1.47 and 24.04, respectively. The nature of the substituent in position 1 has an important influence on the biological activity of these peptides, and the potency of antagonists I-IV (all less potent antagonists than [1-sarcosine,8-threonine]angiotensin II) is very much influenced by the length and branching of the side chain in position 8. The in vivo antagonistic activity of [1-sarcosine,8-O-methylthreonine]angiotensin II is reduced considerably shortening the chain length by 1 C atom as is in V.

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