Collect. Czech. Chem. Commun. 1988, 53, 2519-2536

Partially modified retro-inverso enkephalin analogues containing Gly3Ψ(NH-CO)Phe4 modification, Configurational lability

Michael Choreva, Noemy Gilona, Eli Roubinia, Elizabeth Ackermanb, Dina Levian-Teitelbaumc and Marta Rosind

a Department of Pharmaceutical Chemistry, School of Pharmacy, The Hebrew University, P.O. Box 12065, Jerusalem 91120, Israel
b Department of Anaesthesiology, Hadassah Medical Center, Jerusalem, Israel
c Department of Organic Chemistry, The Hebrew University of Jerusalem, Israel
d Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Israel


Two partially modified retro-inverso analogues of Leu-enkephalin in which the peptide bond between Gly3-Phe4 was reversed resulted from the incorporation of the Gly3ψ(NH-CO)Phe4 unit. The presence of racemic 2-benzylmalonyl residue led to diastereomeric mixtures of analogues; H-Tyr-D-Ala-gGly-(RS)-mPhe-Leu-NH2 (I) and H-Tyr-Gly-gGly-(RS)-mPhe-Leu-NH2 (II). Analogue I was more potent than analogue II in the binding assay, induced guinea pig ileum assay as well as in antinociceptive tests. Both activities were naloxone reversible. No analgesia was observed after subcutaneous (SC) administration of 100 mg/kg of either I or II. The problems related to configurational lability of the 2-alkylmalonyl residues in partially modified retro-inverso analogues is addressed.