Synthesis, receptor binding affinities and conformational properties of cyclic methylenedithioether analogues of angiotensin II.
Cyclic 12-, 13- and 14-membered ring angiotensin II analogues related to disulfides but encompassing methylene-dithioether bridges have been prepared. The affinity data from these derivatives were compared to those from the disulfides. The methylenedithioether analogues displayed good binding affinities to rat liver AT1 receptors although in most cases somewhat lower than their disulfide counterparts. One of the methylenedithioethers with a 13-membered ring system demonstrated the highest binding affinity among the thioethers. Theoretical conformational analysis of model compounds of the two series were performed suggesting a similarity between the disulfide and the corresponding methylenedithioether analogues and also between the ring size homologues. This analysis also suggested that some of the model compounds were prone to adopt inverse gamma-turn conformations, which was further supported by use of NMR spectroscopy of the 12-membered ring analogue in the series. The easily executed methylenedithioether cyclization should constitute a valuable complement to the common disulfide methodology for fine-tuning and for probing the bioactive conformation of peptides.
Lindman
S
S
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden.
Lindeberg
G
G
Gogoll
A
A
Nyberg
F
F
Karlén
A
A
Hallberg
A
A
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides; D008099:Liver / Q000648:ultrastructure; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013440:Sulfides
D004220:Disulfides; D010456:Peptides, Cyclic; D011945:Receptors, Angiotensin; D013440:Sulfides; D000804:Angiotensin II