Biological and conformational studies of [Val4]morphiceptin and [D-Val4]morphiceptin analogs incorporating cis-2-aminocyclopentane carboxylic acid as a peptidomimetic for proline

We report the synthesis, biological activity, and conformational analysis of tetrapeptide analogs related to [Val⁴] morphiceptin and [d -Val⁴]morphiceptin in which the proline at the second position has been replaced with cw-2-aminocyclopentane carboxylic acid (cis-2-Ac⁵c). Since the cis-2-Ac⁵c residue contains a normal amide, only the trans form has been observed about the amide bond between the first and second residues. The cis-2-Ac⁵c is a β amino acid with two chiral centers resulting in two possible configurational isomers, namely (1s, 2R) and (1R, 2S) forms. The analogs containing the (1s, 2R)-Ac⁵c residue show activity at the μ-receptor but are inactive at the δ-receptor, resulting in a high selectivity for the μ-receptor. The (1R, 2S)-Ac⁵c containing analogs are completely inactive at both the μ- and δ-receptors. The conformational analysis indicates that the separation of the aromatic rings of the tyrosine and phenylalanine residues, as expressed by the center-to-center distance, is 10.1-12.7 Å for the preferred conformations of the bioactive analogs containing the (1S, 2R)-Ac⁵c residue while a range of 4.8-7.0 Å is observed for the preferred conformations of the inactive analogs with the (1R, 2S)-Ac⁵c residue. A comparison of the findings from the conformational analysis and biological assays establishes the fact that a relatively large separation of the two aromatic side chains is required for the μ-opioid receptor activity of these molecules. Since the tetrapeptide amides studied in this investigation show similar biological profiles to those of the morphiceptin-related analogs, we have compared the preferred conformations estimated for the cis-2-Ac⁵c containing analogs with those of morphiceptin. One of the low energy conformations calculated for morphiceptin with the cis form about the tyrosine and proline residues has considerable topological similarity with the bioactive analogs containing the (1S, 2R)-Ac⁵c residue, indicating that the cis from about these two residues is required for the biological activity of the morphiceptin-related analogs containing the proline at the second position.