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Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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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
Abstract [en]

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.
Keyword [en]
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
National Category
Organic Chemistry
URN: urn:nbn:se:uu:diva-72679DOI: 10.1021/jm011063aPubMedID: 11960488OAI: oai:DiVA.org:uu-72679DiVA: diva2:100590
Available from: 2007-03-14 Created: 2007-03-14 Last updated: 2012-01-02Bibliographically approved

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Lindeberg, GunnarJohansson, AnjaGogoll, AdolfNyberg, FredKarlen, AndersHallberg, Anders
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