Cyclopropane-derived peptidomimetics. Design, synthesis, and evaluation ofnovel enkephalin analogues

It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling s tudies now suggest that the corresponding cis-cyclopropane dipeptide isoste res could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements o f the Gly(2)-Gly(3) and Phe(4)-Leu(5) dipeptide subunits in Leu-enkephalin (H2N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed to bind to opiod receptors in a conformation containing a beta-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -Xaa Psi[COcpCO]Yaa- an d -Xaa Psi[NHcpNH]Yaa- were developed by a sequence that featured the enant ioselective cyclization of allylic diazoacetates catalyzed by the chiral rh odium complexes Rh-2[(5S)-MEPY](4) and Rh-2[(5R)-MEPY](4). A useful modific ation of the Weinreb amidation procedure was applied to the opening of the intermediate lactones with dipeptides, and a novel method for the synthesis of substituted diaminocyclopropanes was also developed. The Leu-enkephalin analogues were tested in a panel of binding and functional assays, and alt hough those derivatives containing cyclopropane replacements of the Gly2-Gl y3 exhibited low micromolar affinity for the mu-receptor, analogues contain ing such replacements for the Phe(4)-Leu(5) subunit did not bind with signi ficant affinity to any of the opiod receptors. These results are discussed.