Synthesis and analgesic activity of alkylated, reduced and constrained oligoheterocyclic peptidomimetic analogs of Leu-enkephalin

• Published in: Bioorganic & medicinal chemistry letters 2014-09, Vol.24 (18), p.4482-4485
• Main Authors: Hammami, Saoussen, Mighri, Zine, Dooley, Colette T., Nefzi, Adel
• Format: Article
• Language: English
• Subjects: Alkylation; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Combinatorial chemistry; Dose-Response Relationship, Drug; Enkephalin, Leucine - analogs & derivatives; Enkephalin, Leucine - chemistry; Enkephalin, Leucine - pharmacology; Heterocyclic Compounds - chemistry; Humans; Molecular Structure; Oligoheterocyclic peptidomimetics; Opioid receptors; Oxidation-Reduction; Peptidomimetics; Peptidomimetics - chemistry; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, mu - antagonists & inhibitors; Solid-phase synthesis; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.07.090

We report the design and the parallel solid phase synthesis of linear and oligoheterocyclic peptidomimetic analogs of Leu-enkephalin. The described peptidomimetics represent different unique scaffolds that distribute in the space the peptidyl side chains of amino acids essential for biological activity and mimic the bioactive conformation of the Leu-enkephalin peptide. All the compounds were screened in competitive radioligand binding assays to determine their affinities for μ-(MOR), and κ-(KOR) opioid receptors. A reduced analog of Leu-enkephalin TPI1879-26 with activity Ki=60nM for the mu receptor was identified.