Differences in Backbone Structure between Angiotensin II Agonists and Type I Antagonists

Abstract

Type I angiotensin II antagonists with O-methyl-L-homoserine [HSer(gamma-OMe)] and delta-methoxy-L-norvaline [Nva(delta-OMe)] at position 8 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus, and their backbone conformational properties were investigated by nuclear Overhauser effect (NOE) spectroscopy. [Sar1,HSer-(gamma-OMe)8]ANGII, [HSer(gamma-OMe)8]ANGII, [Des1,HSer(gamma-OMe)8]ANGII, [Sar1,Nva(delta-OMe)8]-ANGII, and [Des1,Nva(delta-OMe)8]ANGII had, respectively, the following antagonist activities, pA2: 7.6, 7.5, < 6.0, 7.1, and 6.9. Analogs of [Sar1]ANGII with delta-hydroxy-L-norvaline [Nva(delta-OH)], delta-methoxy-L-norvaline [Nva(delta-OMe)], 4'-carboxyphenylalanine [Phe(4'-COOH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar1,Nva(delta-OH)4]ANGII, [Aib1,Nva(delta-OMe)4]ANGII, [Sar1,DL-Phe(4'-COOH)4]ANGII, and [Sar1,DL-Phe(4'-CF3)4]ANGII had, respectively, agonist activities as follows: 4%, 1.5%, 3%, < 0.1%, and < 0.1%. These data emphasize that replacement of Ile8 in Sarilesin with the higher homologs HSer(gamma-OMe) and Nva(delta-OMe) does not greatly alter the structural requirements necessary for expression of type I antagonist activity, while replacement of the tyrosine hydroxyl in [Sar1]ANGII by the carboxylate or the trifluoromethyl group abolishes activity, suggesting that the tyrosinate pharmacophore cannot be replaced by any negatively charged or electronegative group. Conformational investigation of the ANGII type I antagonists [HSer(gamma-OMe)8]ANGII and [Sar1Nva(delta-OMe)8]ANGII in DMSO by 1D-NOE spectroscopy revealed that the Tyr-Ile-His bend, a conformational property found in ANGII and [Sar1]ANGII (J. Biol. Chem. 1994, 269, 5303) is not present in type I antagonists, providing for the first time an important conformational difference between angiotensin II agonists and type I antagonists.

An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT1 Angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies

“…In 1994, a model of AII based on NMR studies using 2D ROESY techniques in receptor simulating environments has been developed which involves an aromatic ring cluster and consequently a charge relay system formed from the triad of amino acids Tyr4-His6-Phe8 was suggested [52].…”

“…Comparative nuclear magnetic resonance studies of the backbone structure between peptide agonists and antagonists have shown that agonists display ring clustering and form a charge relay system [53] Such clustering is also present to the competitive antagonist [Tyr(OMe)4]AII (sarmesin) which lacks the potential of the charge relay system and the form of the tyrosinate anion which is a strict requirement for agonist activity in the proposed model [54,55]. In addition, the proposed conformation of AII and sarmesin overlay the non-peptide AII receptor antagonist losartan and its analogues when molecular modeling techniques and superimposition studies are applied [28].…”

Biochemical pharmacology of total retro-inverso analogues of bradykinin and angiotensin II: Molecular recognition by G-protein-coupled receptors and angiotensin converting enzyme

“…One possible explanation for the extremely low receptor-binding affinity of TRI 'agonists' is provided by comparative structural studies, which have indicated that precise backbone turn formation is essential for the agonist activity of both BK [21] and AT II [22]. Antagonists, however, may adopt a more extended solution conformation [21,22].…”

Docking and Molecular Dynamics Calculations of Pyrrolidinone Analog MMK16 Bound to COX and LOX Enzymes

“…[11,12,13] Based on the molecular characterization of commercial SARTANs, synthetic peptidic and non-peptidic analogs, a new avenue was explored in an attempt to design and synthesize novel AT 1 antagonists. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Thus, MMK analogs have been synthesized to possess pyrrolidinone as template instead of biphenyltetrazole segment. [29,30] The lack of significant activity of the synthetic molecules as AT 1 antagonists led us to test them as anti-inflammatory drugs since it is well known from the literature that pyrrolidinone analogs have such a property.…”