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Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt(1)]N/OFQ(1-13)
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
Agonist
medicine.medical_specialty
medicine.drug_class
NOP
Socio-culturale
Stimulation of [(35)S]GTPγS binding
Pharmacology
Calcium mobilization
Monkey spinal analgesia
NOP and opioid receptors
PWT2-[Dmt(1)]N/OFQ(1–13)
Receptor binding
Naltrexone
03 medical and health sciences
0302 clinical medicine
In vivo
Internal medicine
medicine
Receptor
Chemistry
digestive, oral, and skin physiology
Receptor antagonist
Nociceptin receptor
030104 developmental biology
Endocrinology
Opioid
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....721eec402428e2ddf006bccc6d811d51