Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13).

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)-NH 2 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)NH 2 (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)-NH 2 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)-NH 2 . 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)-NH 2 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. [ABSTRACT FROM AUTHOR]