DIFFERENCES IN BACKBONE STRUCTURE BETWEEN ANGIOTENSIN-II AGONISTS ANDTYPE-I ANTAGONISTS

Type I angiotensin II antagonists with O-methyl-L-homoserine [HSer(gam ma-OMe)] and delta-methoxy-L-norvaline [Nva(delta-OMe)] at position 8 have been prepared by the solid-phase method, purified by reverse-phas e HPLC, and bioassayed in the rat uterus, and their backbone conformat ional properties were investigated by nuclear Overhauser effect (NOE) spectroscopy. [Sar(1),HSer(gamma-OMe)(8)]ANGII, [HSer(gamma-OMe)(8)]AN GII, [Des(1),HSer(gamma-OMe)8]ANGII, [Sar(1),Nva(delta-OMe)(8)]ANGII, and [Des(1),Nva(delta-OMe)(8)]ANGII had, respectively, the following a ntagonist activities, pA(2): 7.6, 7.5, <6.0, 7.1, and 6.9. Analogs of [Sar(1)]ANGII with delta-hydroxy-L-norvaline [Nva(delta-OH)], delta-me thoxy-L-norvaline [Nva(delta-OMe)], 4'-carboxyphenylalanine [Phe(4'-CO OH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar(1),Nva(delta-OH)(4)]ANGII, [Aib(1),Nva(delta-OMe)(4)]ANGII, [Sar( 1),DL-Phe(4'-COOH)4]ANGII, and [Sar(1),DL-Phe(4'-CF3)(4)]ANGII had, re spectively, agonist activities as follows: 4%, 1.5%, 3%, <0.1%, and <0 .1%. These data emphasize that replacement of Ile(8) in Sarilesin with the higher homologs HSer(gamma-OMe) and Nva(delta-OMe) does not great ly alter the structural requirements necessary for expression of type I antagonist activity, while replacement of the tyrosine hydroxyl in [ Sar(1)]ANGII by the carboxylate or the trifluoromethyl group abolishes activity, suggesting that the tyrosinate pharmacophore cannot be repl aced by any negatively charged or electronegative group. Conformationa l investigation of the ANGII type I antagonists [HSer(gamma-OMe)(8)]AN GII and [Sar(1) Nva(delta-OMe)(8)]ANGII in DMSO by 1D-NOE spectroscopy revealed that the Tyr-Ile-His bend, a conformational property found i n ANGII and [Sar(1)]ANGII (J. Biol. Chem. 1994, 269, 5303) is not pres ent in type I antagonists, providing for the first time an important c onformational difference between angiotensin II agonists and type I an tagonists.