Peptide conformations. 33. Conformational analysis of cyclic enkephalin analogs of the type Tyr‐cyclo‐(‐N ω ‐Xxx‐Gly‐Phe‐Leu‐)*

Four conformationally restricted cyclic enkephalin analogs of the type Tyr‐cyclo(‐Nω ‐Xxx‐Gly‐Phe‐Leu‐) with Xxx = l‐Orn, d‐Orn, l‐Lys and d‐Lys have been synthesized by conventional methods and the conformation of the Bocprotected, the deprotected as well as the des Tyr1 analogs analysed by proton and nitrogen n.m.r. spectroscopy. The assignments, of the resonances were performed by two‐dimensional homo‐ and heteronuclear correlated spectroscopy in the normal (COSY, SECSY) as well as a modified (for the detection of small couplings) version. NOE difference spectroscopy was used to distinguish the amino acid residues with aliphatic side chains. The n.m.r. parameters suggest a rather rigid conformation of the ornithine analogs with two internal NH protons whereas the lysine peptides appear to be more flexible. The structure of the Orn2‐analogs can be described by a Gly3‐CO HN‐Leu5‐γi‐turn and a hydrogen bond Orn2‐CO HN ‐Orn2. The d‐lysine compound seems to include a β‐turn (Gly3‐CO HN‐d‐Lys2). The relation of the different conformational properties of the four cyclic peptides and their biological activities are briefly discussed.