Morphiceptin analogs containing 2‐aminocyclopentane carboxylic acid as a peptidomimetic for proline

Abstract

As part of a program to study the structure-activity relationship of peptide opioids we report the synthesis, conformational characerization and biological activity of four analogs related to morphiceptin in which the proline at position two has been substituted with 2-aminocyclopentane carboxylic acid (.beta.Ac5c). The .beta.Ac5 c residue is a beta amino acid with two chiral centers resulting in four possible configurations; two configurational cis (R,S and S,R) and two configurational trans (R,R and S,S) forms. Utilizing high resolution n.m.r. at 500 MHz and computer simulations with NOE restraints the chirality of the .beta.Ac5 c residues are assigned. The analog containing the R,S-.beta.Ac5 c is active at both the .mu. and .delta.-opioid receptors, with a slight preference for the .mu.-receptor. The (S,R), (S,S), and (R.R) analogs show minimal activity at the .mu.-receptor and are inactive at the .delta.-receptor. A comparison of the bindings from the conformational analysis and biological assays lends insight into the structure-activity relationship of this important peptide opiate.