364635-94-9Relevant academic research and scientific papers
Design, synthesis and biological evaluation of cyclic angiotensin II analogues with 3,5 side-chain bridges: Role of C-terminal aromatic residue and ring cluster for activity and implications in the drug design of AT1 non-peptide antagonists
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
, p. 2627 - 2633 (2007/10/03)
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.
Synthesis and study of a cyclic angiotensin II antagonist analogue reveals the role of π*-π* interactions in the C-terminal aromatic residue for agonist activity and its structure resemblance with AT1 non-peptide antagonists
Polevaya, Ludmila,Mavromoustakos, Thomas,Zoumboulakis, Panagiotis,Grdadolnik, Simona Golic,Roumelioti, Panagiota,Giatas, Nektarios,Mutule, Ilze,Keivish, Tatjana,Vlahakos, Demetrios V,Iliodromitis, Efstathios K,Kremastinos, Dimitrios Th,Matsoukas, John
, p. 1639 - 1647 (2007/10/03)
The novel amide linked Angiotensin II (ANG II) cyclic analogue cyclo(3, 5)-[Sar1-Lys3-Glu5-Ile8] ANG II (18) has been designed, synthesized and bioassayed in anesthetized rabbits. The constrained cyclic analogue with a lactam amide bridge linking a Lys-Glu pair at positions 3 and 5 and possessing Ile at position 8, was synthesized by solution procedure using the maximum protection strategy. This analogue was found to be inhibitor of Angiotensin II. NMR spectroscopy coupled with computational analysis showed clustering between the side chains of the key aminoacids Tyr4-His6-Ile8 similar to that observed with ANG II. The obtained data show that only π*-π* interactions observed in ANG II or its superagonist Sar1 [ANG II] are missing. Therefore, it can be concluded that these interactions are essential for agonist activity. Conformational analysis comparisons between AT1 antagonists losartan, eprosartan and irbesartan with C-terminal segment of cyclic compound 18 revealed structural similarities. Copyright
