SYNTHESIS AND BIOLOGICAL-ACTIVITY OF A NOVEL METHYLAMINE-BRIDGED ENKEPHALIN ANALOG (MABE) - A NEW ROUTE TO CYCLIC-PEPTIDES AND PEPTIDOMIMETICS

The synthesis and biological activity of a methylamine-bridged enkepha lin analogue (MABE) is presented. The key step in the synthesis of the target compound involves the ring opening of Cbz-D-serine beta-lacton e with Boc-Phe-NHCH2CH2NHCH3. Further synthetic elaboration of the res ulting building block yielded compound 1 (MABE, Tyr-c[(NbetaCH3)-D-A(2 )pr-Gly-Phe-NHCH2CH2-], where A(2)pr is a 2,3-diaminopropionic acid re sidue). Utilizing a combination of NMR and molecular modeling, the str ucture-biological activity relationships for compound 1 were studied. Using an in vitro isolated receptor assay, MABE was found to have affi nities for isolated mu, delta, and kappa opioid receptors of 1.6, 2.1, and 340 nM, respectively. By an in vivo thermal escape assay, MABE wa s found to have an ED50 of 0.027 mu g in the rat when administered int rathecally. This effect was reversed by naloxone. :By comparison, DAMG O, morphine, and DPDPE were found to yield ED50 values of 0.14, 2.4, a nd 54 mu g, respectively, in the same assay.