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

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.

Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

“…It has been shown that ROS activates GRP78/PERK signal transduction, which induces apoptosis via ER stress in cervical cancer cells [39]. This finding is consistent with a recent report that luteolin, a common dietary flavonoid, induces the ER stress response and mitochondrial dysfunction by increasing intracellular ROS levels in glioblastoma cells [40]. Another study reported that JS-K, a glutathione S transferase (GST)-activated nitric oxide (NO) donor prodrug, promotes apoptosis by inducing ROS production in human prostate cancer cells [41].…”

Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking

“…Notably, whereas some mixed MOR-NOP receptor peptide ligands were reported in the literature as potential analgesics [ 55 , 56 , 57 , 58 ], their antinociceptive properties were described only in acute thermal nociception (tail-flick test) when injected i.t. or i.c.v.…”

Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic

“…59 Collectively, this evidence strongly suggests that mixed NOP/opioid receptor agonists may have therapeutic potential as novel analgesics. Some compounds with the above pharmacological profile have been reported in the literature including the peptides [Dmt 1 ]N/OFQ(1e13)-NH 2 60 and its tetrameric deriva- 61 DeNo (a dermorphin-N/OFQ chimeric peptide), 62 and some non-peptide compounds SR16435, SR16507, and SR14150 (reviewed by Toll and colleagues 4 ) that display variable potency and efficacy at NOP and mu receptors. Moreover, BU08028 is a buprenorphine derivative that displayed high affinity for NOP and opioid receptors.…”