| Literature DB >> 27871910 |
Maria Camilla Cerlesi1, Huiping Ding2, Mark F Bird3, Norikazu Kiguchi2, Federica Ferrari1, Davide Malfacini1, Anna Rizzi1, Chiara Ruzza1, David G Lambert3, Mei-Chuan Ko2, Girolamo Calo1, Remo Guerrini4.
Abstract
An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt1]N/OFQ(1-13)-NH2 acts as a universal agonist for nociceptin/orphanin FQ (N/OFQ) and classical opioid receptors. The present study investigated the pharmacological profile of the PWT derivative of [Dmt1]N/OFQ(1-13)NH2 (PWT2-[Dmt1]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt1] mimicked the effects of [Dmt1]N/OFQ(1-13)-NH2 displaying full agonist activity, similar affinity/potency and selectivity at human recombinant N/OFQ (NOP) and opioid receptors in receptor binding, stimulation of [35S]GTPγS binding, calcium mobilization in cells expressing chimeric G proteins, and BRET studies for measuring receptor/G-protein and receptor/β-arrestin 2 interaction. In vivo in monkeys PWT2-[Dmt1] elicited dose-dependent and robust antinociceptive effects being more potent and longer lasting than [Dmt1]N/OFQ(1-13)-NH2. The analgesic action of PWT2-[Dmt1] was sensitive to the NOP receptor antagonist J-113397, but not naltrexone. Thus, the present study demonstrated that the tetrabranched derivative of [Dmt1]N/OFQ(1-13)-NH2 obtained with the PWT technology maintains the in vitro pharmacological profile of the parent peptide but displays higher potency and longer lasting action in vivo.Entities:
Keywords: Calcium mobilization; Monkey spinal analgesia; NOP and opioid receptors; PWT2-[Dmt(1)]N/OFQ(1–13); Receptor binding; Stimulation of [(35)S]GTPγS binding
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Year: 2016 PMID： 27871910 PMCID： PMC5183561 DOI： 10.1016/j.ejphar.2016.11.026
Source DB: PubMed Journal: Eur J Pharmacol ISSN： 0014-2999 Impact factor: 4.432