| Title | Type I angiotensin II antagonists | |
| Authors | G. Agelis1, A. Wahhab2, J. Hondrelis1, R. Yamdagni1, Q. Wu3, R. Ganter2, J. Smith4, G.J. Moore2 and J.M. Matsoukas1
1. Department of Chemistry, University of Patras, 26110 Patras, Greece 2. Pharmacology and Therapeutics, University of Calgary, T2N 4N1 Calgary, Canada 3. Department of Chemistry, University of Calgary, T2N 1N4 Calgary, Canada 4. Department of Chemistry, University of Exeter, EX4 4QD Exeter, England |
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| Citation | Agelis, G., Wahhab, A., Hondrelis, J., Yamdagni, R., Wu, Q., et al.: Type I angiotensin II antagonists, Epitheorese Klin. Farmakol. Farmakokinet. 9(2-3): 59-61 (1995) | |
| Publication Date | 1995 | |
| Full Text Language | English | |
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| Keywords | Angiotensin II antagonists, conformational properties, NMR spectroscopy. | |
| Other Terms | review article | |
| Summary | Type I Angiotensin II (ANGII) antagonists with γ-methoxy-L-Homoserine, [HSer(γ-OMe)] and δ-methoxy-L-Norvatine, [Nva (δ-OMe)] at position 8 have been prepared by the solid phase method, purified by reverse-phase HPLC and bioassayed in the rat uterus. [Sar1,HSer(γ-OMe)8ANGII, [HSer(γ-OMe)8]ANGII, [Des¹, HSer(γ-OMe)8]ANGII, [Des1, Nva(δ-OMe)8]ANGII, had respectively the following antagonist activities, pA2: 7.6, 7.5, <6.0 and 6.9. Analogues of [Sar¹]ANGΙΙ with δ-hydroxy-L-Norvaline, [Nva(δ– OH)], δ-methoxy-L-Norvaline, [Nva(δ-OMe)], 4- (carboxy) phenylalanine, [Phe(4COOH) and 4′- (trifluoromethyl) phenylalanine, [Phe(4’CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar1,Nva(δ– OH)4]ANGII, [Aib1,Nva(δ-OMe)4]ANGII, [Sar1,DL- Phe (4’CF3)4]]ANGΙΙ, had respectively agonist activities as follows: 4%, 1.5% and <0.1%. These data emphasize that replacement of ΙΙe8 in Sarilesin with the higher homologs Hser (γ-OMe) and Nva(δ-OMe), does not greatly alter the structural requirements necessary for expression of type I antagonist activity while replacement of the Tyrosine hydroxyl in [Sar¹]ANGII by the carboxylate or the trifluoromethyl group, abolishes activity suggesting that the Tyr hydroxyl pharmacophore is uniquely involved in receptor activation. Conformational investigation of the ANGII type I antagonist [HSer(γ-OMe)8]ANGII, in DMSO by 1D-Nuclear Overhauser Effect (NOE) Spectroscopy, revealed that the Tyr-ΙΙe-His bend, a conformational property found in ANGII and [Sar¹]ANGII, is not present in type I antagonists, providing an important conformational difference between agonists and type I antagonists. | |
| References | 1. Page, L.H.: Hypertension mechanisms, p. 347, Harcourt Brace Jovanovich, New York, 1987
2. Khosla, M.C., Smedy, R.R., Bumpus, F.M.: In: Hand-book of Experimental Pharmacology (Eds. Page Ι, H., Bumpus, F.M.), p. 126, Springer-Verlag, New York, 37, 1974 3. Matsoukas, J.M., Agelis, G., Hondrelis, J., Yamdagni, R., Wu, Q., Ganter, R., Smith, J.R., Moore, D., Moore, G.J.: J. Med. Chem. 36: 904 (1993) 4. Matsoukas, J.M., Hondrelis, J., Keramida, M., Mavromoustakos, T., Makriyannis, A., Yamdagni, R., Wu, Q., Moore, G.J.: J. Biol. Chem. 269: 5303 (1994) |
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Online ISSN 1011-6575
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