Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor
2002 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 45, no 9, 1767-1777 p.Article in journal (Refereed) Published
Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]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 CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]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 AT(1) 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.
Place, publisher, year, edition, pages
2002. Vol. 45, no 9, 1767-1777 p.
Angiotensin II/*analogs & derivatives/*chemical synthesis/chemistry/pharmacology, Animals, Aorta/drug effects/physiology, Binding; Competitive, Chromatography; High Pressure Liquid, In Vitro, Liver/metabolism, Male, Models; Molecular, Molecular Conformation, Muscle Contraction, Muscle; Smooth; Vascular/drug effects/physiology, Peptide Fragments/*chemical synthesis/chemistry/pharmacology, Peptides; Cyclic/*chemical synthesis/chemistry/pharmacology, Rabbits, Radioligand Assay, Rats, Receptor; Angiotensin; Type 1, Receptors; Angiotensin/*agonists/metabolism, Research Support; Non-U.S. Gov't, Stereoisomerism, Structure-Activity Relationship, Sulfides/*chemical synthesis/chemistry/pharmacology, Vinyl Compounds/*chemical synthesis/chemistry/pharmacology
IdentifiersURN: urn:nbn:se:uu:diva-72679DOI: 10.1021/jm011063aPubMedID: 11960488OAI: oai:DiVA.org:uu-72679DiVA: diva2:100590