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.
The novel amide linked angiotensin II (ANG II) cyclic analogues: gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Ile(8)] ANG II (I) and gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Phe(8)] 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 AT(1) non-peptide mimetic losartan probably because it lacks to mimic the orientation of tetrazole and the pharmacophore segments of butyl chain and imidazole ring.
Roumelioti
Panagiota
P
Department of Chemistry, University of Patras, 26500, Patras, Greece.
Polevaya
Ludmila
L
Zoumpoulakis
Panagiotis
P
Giatas
Nektarios
N
Mutule
Ilze
I
Keivish
Tatjana
T
Zoga
Anastasia
A
Vlahakos
Demetrios
D
Iliodromitis
E
E
Kremastinos
Demetrios
D
Grdadolnik
Simona Golic
SG
Mavromoustakos
Thomas
T
Matsoukas
John
J
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D010456:Peptides, Cyclic; D000804:Angiotensin II