Synthesis of a novel side-chain to side-chain cyclized enkephalin analogue containing a carbonyl bridge

A novel type of cyclic opioid peptide analogue, cyclo[N epsilon,N epsilon'-carbonyl-D-Lys2,Lys5]enkephalinamide, was prepared from a linear precursor peptide. The peptide was synthesized on the Merrified resin and also by a combination of the solid-phase technique and the classical method in solution. In both cases the cyclization was performed by reaction of bis(4-nitrophenyl)carbonate with the free side-chain amino groups of the two lysine residues. The described method permits the convenient preparation of novel peptide analogues cyclized via a ureido group incorporating the side-chain amino groups of two alpha, omega-diamino acid residues. The cyclic enkephalin analogue containing a 21-membered ring structure showed preference for mu over delta opioid receptors in opioid bioassays in vitro.