Highly potent side-chain to side-chain cyclized enkephalin analogues containing a carbonyl bridge: Synthesis, biology and conformation

Six novel cyclic enkephalin analogues have been synthesized. Cyclization of the linear peptides containing basic amino acid residues in position 2 and 5 was achieved by treatment with bis(4-nitrophenyl)carbonate. It was found that some of the compounds exibit unusually high mu -opioid activity in th e guinea pig ileum (GPI) assay. The 18-membered analogue cyclo(N-epsilon.N- beta'-carbonyl-D-Lys(2),Dap(5))- enkephalinamide turned out to be one of th e most potent mu -agonists reported so far. NMR spectra of the peptides wer e recorded and structural parameters were determined. The conformational sp ace was exhaustively examined for each of them using the electrostatically driven Monte Carlo method. Each peptide was finally described as an ensembl e of conformations. A model of the bioactive conformation of this class of opioid peptides was proposed. Copyright (C) 2001 European Peptide Society a nd John Wiley & Sons, Ltd.