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

Abstract

It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding cis- cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly2-Gly3 and Phe4-Leu5 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 β-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -XaaΨ[COcpCO]Yaa- and -XaaΨ[NHcpNH]Yaa-were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates catalyzed by the chiral rhodium complexes Rh2[(5S)-MEPY]4 and Rh2[(5R)-MEPY]4. A useful modification 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 although those derivatives containing cyclopropane replacements of the Gly2-Gly3 exhibited low micromolar affinity for the μ- receptor, analogues containing such replacements for the Phe4-Leu5 subunit did not bind with significant affinity to any of the opiod receptors. These results are discussed.