Design, Synthesis And Pharmacological Properties Of A Novel Deltorphin â…¡-melatonin Chimeric Peptide

To elucidate the mechanism of analgesic effects induced by Melatonin (MT) and Deltorphins (Dels), and to develop novel analgesic drugs that can be more potency than natural or traditional drugs, we designed, synthesized and characterized deltorphin II by Fmoc solid-phase peptide synthesis method and the chimeric peptide (named Del II-Mt) containing the amide linkage that were shared by the C-terminal amide group of deltorphin II (Del II) and N-acyl group of melatonin through amidation reaction, deltorphin I (Del I) and the chimeric peptide (named Del I-Mt) were synthesized by other co-wokers formerly. All the peptides were purified by reverse-phase high-performance liquid chromatography (RP-HPLC) and further analysized by analytical RP-HPLC and characterized by ESI-MS. Intracerebroventricular (i.c.v) administration of Del I-Mt (5,50 nmol/kg) [Y (D-A) FDVVG-MT] or Del II-Mt (5,50 nmol/kg) [Y (D-A) FEVVG-MT] produced more profound analgesic effect than Deltorphins (Del I or Del II alone), and longer acting analgesic effect than cocktails containing Dels (50 nmol/kg) and MT (50 nmol/kg) as monitored by the tail-flick test. Interestingly, Dels-Mt showed lower affinity and selectivity forδreceptor than Dels alone by in vitro assay. Naloxone co-administration (i.c.v,100 nmol/Kg) could totally block the analgesic effects induced by both the chimeric peptides. While, luzindole (specific antagonist of melatonin receptor, i.c.v,250 nmol/Kg) could only decrease the effects to the level same as the effects caused by deltorphins alone. These results confirmed that Del I-Mt and Del II-Mt could produce significant, long-lasting analgesic effect, and co-activate 8 opioid receptors system (DORs) and melatonin receptor system (MTRs) as a dual receptors angoist, as well as exploring the relationship between MTRs and DORs in pain regulation.