Libraries of opiate and anti-opiate peptidomimetics containing 2,3-methanoleucine.
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abstract
A library of 96 peptides/peptidomimetics was prepared, in which half was based on the YGGFL-NH2 sequence, while the remainder were derivatives of a presumed anti-opiate peptide, YGGFLRF-NH2. Of the 48 compounds in each half of the library, 32 contained a stereoisomer of 2,3-methanoleucine substituted for Leu5. Binding of the YGGFL-NH2 derivatives to the mu- and delta-opioid receptors, and to the anti-beta-endorphin monoclonal antibody (clone 3E7), indicated any change at the Leu5 had little effect on the binding when compared with modifications to the YGGF-sequence. Conversely, cyclo-Leu residues did alter the binding of YGGFLRF-NH2 derivatives when substituted for Leu5. Of these 32 peptidomimetics, three derivatives of 2S,3S-cyclo-Leu had relatively low Ki values for binding to an NPFF receptor. Differences between the outcome of the screens were interpreted in terms of the position of the cyclo-Leu residue in the two sequences.