Bioorganic and Medicinal Chemistry Letters p. 2627 - 2633 (2002)
Update date:2022-07-29
Topics: Synthesis Biological Evaluation Design
Roumelioti, Panagiota
Polevaya, Ludmila
Zoumpoulakis, Panagiotis
Giatas, Nektarios
Mutule, Ilze
Keivish, Tatjana
Zoga, Anastasia
Vlahakos, Demetrios
Iliodromitis
Kremastinos, Demetrios
Grdadolnik, Simona Golic
Mavromoustakos, Thomas
Matsoukas, John
The novel amide linked Angiotensin II (ANG II) cyclic analogues: γ,ε-cyclo(3, 5)-[Sar1-Glu3-Lys5-Ile8] ANG II (I) and γ, ε-cyclo(3, 5)-[Sar1-Glu3-Lys5-Phe8] ANG II (II) have been designed, synthesized and bioassayed in anesthetized rabbits in order to unravel structural ring cluster characteristics important for receptor activation. Analogue I with Ile at position 8 was an inhibitor of Angiotensin II while analogue II with Phe at position 8 was found to be an agonist. Similar results were reported for cyclic compounds that have reversed the linking between positions 3 and 5. The overall results show that positions 3 and 5 do not govern the biological activity of the synthetic analogues. It also appears that the aromatic ring cluster (Tyr-His-Phe) in agonist peptides is an essential stereo-electronic feature for Angiotensin II to exert its biological activity. A non-peptide mimetic of ANG II, 1-[2′-[(N-benzyl)tetrazol-5-yl]biphenyl-4-yl]methyl]-2- hydroxymethylbenzimidazole (BZI8) has been designed and synthesized. This molecule is more rigid and much less active than AT1 non-peptide mimetic losartan probably because it lacks to mimic the orientation of tetrazole and the pharmacophore segments of butyl chain and imidazole ring.
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Doi:10.1021/jo00975a009
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