Activity Profiles of Linear, Cyclic Monomer and Cyclic Dimer of Enkephalin

Abstract

The cyclic dimers of enkephalin were isolated as minor components during the solution synthesis of the corresponding cyclic monomers. The ratio of cyclic dimer to monomer was approximately 1:4 from the percent of yields. In the receptor binding assay of two cyclic dimmers, (Tyr2-C[D-Glu-Phe-gPhe]2 6, Tyr2-C[D-AspPhe-gPhe-rLeu]2 8), both analogs exhibited the high preference for δ receptor compared to monocyclic counterparts. In the nociceptive activity, both showed about 5 times less potent than the cyclic monomers. The repeated synthesis of 14-membered cyclic analog, Tyr-C[D-Glu-Phe-gPhe-D-rLeu] 14, which was known as having three distinct cis-trans isomers, gave rise to apparently different conformational analog arousing only trans isomer. In the receptor binding assay, it showed tremendously high selectivity toward μ receptor (δ/μ =