Structure-Activity Relationships of 13- and 14-Membered Cyclic Partial Retro-Inverso Pentapeptides Related to Enkephalin

Abstract

A series of 13and 14-membered cyclic enkephalin analogs based on the moderately μ selective prototype compound Tyr-C[D-A2bu-Gly-Phe-Leu] 8a were synthesized to investigate the structure-activity relationship. The modifications of sequence were mainly focused on two positions 3 and 5, critical for the selective recognition for μ and δ opioid receptors. The substitution of hydrophobic Leu with hydrophilic Asp derivatives led to Tyr-C[D-A2bu-Gly-PheAsp(N-Me)] 7 and Tyr-C[D-Glu-Phe-gPhe-rAsp(O-Me)] 5, the peptides with a large affinity losses at both μ and δ receptors. The substitution of Phe with Gly led to Tyr-C[D-Glu-Gly-gPhe-rLeu] 3 and Tyr-C[D-Glu-Gly-gPhe-DrLeu] 4, the peptides with large affinity losses at μ receptors, indicating the critical role of phenyl ring of Phe for μ receptor affinities. One atom reduction of the ring size from 14-membered analogs Tyr-C[D-Glu-Phe-gPhe-(L and D)rLeu] 6a, 6b to 13-membered analogs Tyr-C[D-Asp-Phe-gPhe-(L and D)-rLeu] 1, 2 reduced the affinity at both μ and δ receptors, but increased the potency in the nociceptive assay, indicating the ring constrain is attributed to high nociceptive potency of the analogs. For the influence of Dor L-chirality of Leu5 on the receptor selectivity, regardless of chirality and ring size, all cyclic diastereomers displayed marked μ selectivity with low potencies at the δ receptor. The retroinverso analogs display similar or more active at μ receptor, but less active at δ receptor than the parent analogs.