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Rigid amino acid surrogates can be used to reduce the conformational space available to peptidomimetics.1-3 Unlike a-or /3-methyl amino acids,4-8 2,3-methano amino acids9 (e.g., 25, have rigidly defined x1 11orientations. Consequently, 2,3-methano amino acids should have marked effects on secondary structures. For a few of these "methanologs", Ramachandran plots have been calculated to visualize the local and \p restrictions,10-12 and solid-state structures of some simple derivatives have been deduced via crystallography.1314 Nevertheless, the effects of substituted 2,3methano amino acids on solution secondary structures remain almost15 completely unexplored. This paper describes favored solution-phase conformations of mimics of the anti-opiate16'17 peptide Phe-Mel-Arg-Phe-NH2, wherein methionine has been substituted by 25,35-cyclo-Met. FMOC-protected 25,35-cyclo-Met was prepared via a modification18 of our original synthesis,19 and incorporated into peptidomimetic 1 using a solid-phase approach. NMR studies were performed at 400 MHz, at 10 mM (1) Degrado, W. F.