Synthesis, receptor binding affinities and conformational properties of cyclic methylenedithioether analogues of angiotensin II

Cyclic 13-, 13- and 14-membered ring angiotensin II analogues related to di sulfides but encompassing methylene-dithioether bridges have been prepared. The affinity data from these derivatives were compared to those from the d isulfides. The methylenedithioether analogues displayed good binding affini ties to rat liver AT(1) receptors although in most cases somewhat lower tha n their disulfide counterparts. One of the methylenedithioethers with a 13- membered ring system demonstrated the highest binding affinity among the th ioethers. Theoretical conformational analysis of model compounds of the two series were performed suggesting a similarity between the disulfide and th e corresponding methylenedithioether analogues and also between the ring si ze homologues. This analysis also suggested that some of the model compound s were prone to adopt inverse gamma -turn conformations, which was further supported by use of NMR spectroscopy of the 12-membered ring analogue in th e series. The easily executed methylenedithioether cyclization should const itute a valuable complement to the common disulfide methodology for fine-tu ning and for probing the bioactive conformation of peptides. (C) 2001 Elsev ier Science Ltd. All rights reserved.