Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13)
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- 作者：Maria Camilla Cerlesia ; Huiping Dingb ; Mark F. Birdc ; Norikazu Kiguchib ; Federica Ferraria ; Davide Malfacinia ; Anna Rizzia ; Chiara Ruzzaa ; David G. Lambertc ; Mei-Chuan Kob ; Girolamo Caloa ; ; Remo Guerrinid
- 关键词：PWT2-[Dmt1]N/OFQ(1&ndash ; 13) ; NOP and opioid receptors ; Receptor binding ; Stimulation of [35S]GTPγS binding ; Calcium mobilization ; Monkey spinal analgesia
- 刊名：European Journal of Pharmacology
- 出版年：2017
- 出版时间：5 January 2017
- 年：2017
- 卷：794
- 期：Complete
- 页码：115-126
- 全文大小：1292 K
- 卷排序：794
文摘
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.