[$\text{D}\text{-}\text{Pen}{}^2\text{,}\text{L}\text{-}\text{cys}{}^5\text{]}\text{enkephalinamide and}\text{[}\text{D}\text{-}\text{pen}{}^2\text{,}\text{D}\text{-}\text{cys}{}^5\text{]}\text{enkephalinamide}$, conformationally constrained cyclic enkephalinamide analogs with delta receptor specificity

Abstract

The conformationally constrained cyclic enkephalin analogs, [$\text{2-}\text{D}\text{-}\text{penicillamine}$, $\text{5-}\text{L}\text{-}\text{cysteine}\text{]-}\text{and}\text{[2-}\text{D}\text{-}\text{penicillamine}\text{, 5-}\text{D}\text{-}\text{cysteine]enkephalinamide}$ were synthesized and their biological activities investigated. Both analogs effectively induced thermal analgesia as measured by the $\text{in}\text{vivo}$ 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] [$\text{D}\text{-}\text{Ala}{}^2\text{,}\text{D}\text{-}\text{Leu}{}^5\text{]}\text{enkephalin}$ 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 $\text{5-}\text{L}\text{-}\text{cysteine}$ containing analog was more potent than the $\text{5-}\text{D}\text{-}\text{cysteine}$ analog in all the $\text{in}\text{vitro}$ 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.