title: Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Johannesson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindeberg
authors.forename: Anja
authors.initials: A
authors.lastname: Johansson
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Nikiforovich
authors.forename: Adolf
authors.initials: A
authors.lastname: Gogoll
authors.forename: Barbro
authors.initials: B
authors.lastname: Synnergren
authors.forename: Madeleine
authors.initials: M
authors.lastname: Le Grèves
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D010456:Peptides, Cyclic; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013440:Sulfides; D014753:Vinyl Compounds; D000804:Angiotensin II