Dehydro-enkephalins. Part 7. A potent dehydroleucine-enkephalin resistant to carboxypeptidase

Abstract

To preserve the enkephalin-like properties together with resistance to enzymatic degradation, we have synthesized unsaturated analogues of leucine enkephalin, containing dehydroleucine (ΔLeu⁵) in the Z-configuration (isopropyl and CO, trans) at the C-terminus. The ΔLeu unit was introduced by the N-chlorination/dehydrochlorination method. The peptides [D-Ala²,ΔLeu⁵]- and [ΔLeu⁵]-enkephalins were completely resistant to carboxypeptidase Y. In the radioligand binding assays, [D-Ala,²ΔLeu⁵]enkephalin displayed a greater affinity for the δ-enkephalin receptor binding sites. In particular, this dehydroenkephalin was almost four times more active than its saturated [D-Ala²,D-Leu²]enkephalin in the assay using [³H] etorphine as tracer. It is suggested that the high δ-selectivity of [D-Ala²,ΔLeu⁵]enkephalin may be responsible for a moderate in vivo analgesia effect.