Synthesis and study of a cyclic angiotensin II antagonist analogue reveals the role of pi*--pi* interactions in the C-terminal aromatic residue for agonist activity and its structure resemblance with AT(1) non-peptide antagonists.
The novel amide linked Angiotensin II (ANG II) cyclic analogue cyclo(3, 5) -[Sar(1)-Lys(3)-Glu(5)-Ile(8)] 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 Tyr(4)-His(6)-Ile(8) similar to that observed with ANG II. The obtained data show that only pi*--pi* interactions observed in ANG II or its superagonist Sar(1) [ANG II] are missing. Therefore, it can be concluded that these interactions are essential for agonist activity. Conformational analysis comparisons between AT(1) antagonists losartan, eprosartan and irbesartan with C-terminal segment of cyclic compound 18 revealed structural similarities.
Polevaya
L
L
Laboratory of Peptide Chemistry, Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia.
Mavromoustakos
T
T
Zoumboulakis
P
P
Golic Grdadolnik
S
S
Roumelioti
P
P
Giatas
N
N
Mutule
I
I
Keivish
T
T
Vlahakos
D V
DV
Iliodromitis
E K
EK
Kremastinos
D T
DT
Matsoukas
J
J
D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D001671:Biochemistry / Q000379:methods; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D000077405:Irbesartan; D019808:Losartan / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes
D000179:Acrylates; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D010456:Peptides, Cyclic; D013777:Tetrazoles; D013876:Thiophenes; C435828:cyclo(3,5)-(Sar(1)-Lys(3)-Glu(5)-Ile(8))ANG II; D000804:Angiotensin II; C068373:eprosartan; D000077405:Irbesartan; D019808:Losartan