[D-Pen², L-cys⁵]enkephalinamide and [D-pen², D-cys⁵]enkephalinamide, conformationally constrained cyclic enkephalinamide analogs with delta receptor specificity

The conformationally constrained cyclic enkephalin analogs, [2-D-penicillamine, 5-L-cysteine]- and [2-D-penicillamine, 5-D-cysteine]enkephalinamide were synthesized and their biological activities investigated. Both analogs effectively induced thermal analgesia as measured by the in vivo hot plate test. Both analogs were effective in inhibiting muscle contractions in the guinea pig ileum and mouse vas deferens assay systems and were shown to displace both [³H]naloxone and [³H] [D-Ala², D-Leu⁵]enkephalin from rat brain receptor preparations. The analogs exhibited a significant preference for δ-receptors over μ-receptors, an unusual finding for enkephalinamide derivatives. In addition the 5-L-cysteine containing analog was more potent than the 5-D-cysteine analog in all the in vitro assays with the exception of the guinea pig ileum system. These uncommon results are attributed to the conformational constraints imposed by the cyclization via a disulfide and by the rigidizing effect of the penicillamine.