An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt(1)]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 [Dmt(1)]N/OFQ(1-13)NH2 (PWT2-[Dmt(1)]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt(1)] mimicked the effects of [Dmt(1)]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 [(35)S]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-[Dmt(1)] elicited dose-dependent and robust antinociceptive effects being more potent and longer lasting than [Dmt(1)]N/OFQ(1-13)-NH2. The analgesic action of PWT2-[Dmt(1)] was sensitive to the NOP receptor antagonist J-113397, but not naltrexone. Thus, the present study demonstrated that the tetrabranched derivative of [Dmt(1)]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.
Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt(1)]N/OFQ(1-13)
CERLESI, Maria CamillaPrimo
;FERRARI, Federica;MALFACINI, Davide;RIZZI, Anna;RUZZA, Chiara;CALO', Girolamo
Penultimo
;GUERRINI, RemoUltimo
2017
Abstract
An innovative chemical strategy named peptide welding technology (PWT) has been developed for the facile synthesis of tetrabranched peptides. [Dmt(1)]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 [Dmt(1)]N/OFQ(1-13)NH2 (PWT2-[Dmt(1)]) in several assays in vitro and in vivo after spinal administration in monkeys subjected to the tail withdrawal assay. PWT2-[Dmt(1)] mimicked the effects of [Dmt(1)]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 [(35)S]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-[Dmt(1)] elicited dose-dependent and robust antinociceptive effects being more potent and longer lasting than [Dmt(1)]N/OFQ(1-13)-NH2. The analgesic action of PWT2-[Dmt(1)] was sensitive to the NOP receptor antagonist J-113397, but not naltrexone. Thus, the present study demonstrated that the tetrabranched derivative of [Dmt(1)]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.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
