Vinyl Sulfide Cyclized Analogues of Angiotensin II with High Affinity and Full Agonist Activity at the AT1 Receptor

• Published in: Journal of medicinal chemistry Vol. 45; no. 9; pp. 1767 - 1777
• Main Authors: Johannesson, Petra, Lindeberg, Gunnar, Johansson, Anja, Nikiforovich, Gregory V, Gogoll, Adolf, Synnergren, Barbro, Le Grèves, Madeleine, Nyberg, Fred, Karlén, Anders, Hallberg, Anders
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.04.2002
• Subjects: Biological and medical sciences; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Agonist; Rat; Cyclic peptides; Enethiol sulfide; Liver; Rabbit; Smooth muscle; Selectivity; Modeling; Octapeptide; Structure activity relation; Blood vessel; Molecular model; Force field method; Peptidergic receptor; Aorta; Angiotensin II; Chemical synthesis; Rodentia; AT1 angiotensin receptor; Lagomorpha; Muscle contraction; In vitro; Vertebrata; Mammalia; Sulfur peptide; Animal; Affinity; Peptide synthesis; Solid phase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm011063a

Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy3,5]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH2−S−S element of the AT1 receptor agonist c[Hcy3,5]Ang II has been displaced by a bioisosteric three-atom S−CHCH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy3,5]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K i values less than 2 nM and exerted full agonism at the AT1 receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.