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 11 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. (C) 2002 Published by Elsevier Science Ltd.

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.

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.

The novel amide linked Angiotensin II cyclic analogue c-(3,5)-[Sar1-Lys3-Glu5-Ile8]-ANG II (Figure 1) has been designed, synthesized and bioassayed in anesthetized rabbits. The aim of this work was to investigate furthermore the role of a ring cluster receptor conformation in agonist activity and shed light to intriguing differences in activity and conformation upon replacement of aromatic residue Phe with aliphatic Ile. This replacement produces an antagonist, and the cyclization between 3 and 5 positions does not affect the antagonist activity. The constrained cyclic analogue with a lactam amide bridge linking a Lys-Glu pair at positions 3 and 5 and Ile at position 8, was synthesized by solution procedure using the maximum protection strategy. NMR spectroscopy coupled with computational analysis was performed in order to establish the significance of π*-π* interactions. In addition, conformational analysis of non-peptide AT1 antagonists is performed in an attempt to study their stereoelectronic similarities with such a cluster.