Synthesis of angiotensin II analogues by incorporating beta-homotyrosine or beta-homoisoleucine residues.
[1-Sarcosine,4-beta-homotyrosine]-(I), [5-beta-homoisoleucine]-(II), and [1-sarcosine,5-beta-homoisoleucine]angiotensin II (III) were synthesized by Merrifield's solid-phase procedure to study the effect of pressor activity and duration of action. The analogues I--III possessed, respectively, 1.98, 2.82, and 29.2% pressor activity of angiotensin II (vagotomized, ganglion-blocked rats by single-injection procedure) and duration of action of 5.5, 6.7, and 4.7 min; the comparative duration of action of an equipressor dose of angiotensin II was 5.2, 6.3, and 5.3 min, respectively. When incubated with leucine aminopeptidase, degradation of II was as fast as that of angiotensin II; this degradation became considerably slower when position 1 was replaced with sarcosine. Incubation of all these analogues with chymotrypsin showed very little or no degradation up to 3 h. The results indicate that an increase in the chain length by one carbon atom in position 4 or 5 of angiotensin II increased resistance to degradation by chymotrypsin without any increase in in vivo duration of action. Further, all analogues showed low pressor activity.
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002918:Chymotrypsin / Q000378:metabolism; D007532:Isoleucine; D007931:Leucyl Aminopeptidase / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors; D014443:Tyrosine
D007532:Isoleucine; D000804:Angiotensin II; D014443:Tyrosine; D007931:Leucyl Aminopeptidase; D002918:Chymotrypsin