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Novel Mixed NOP/Opioid Receptor Peptide Agonists
- Source :
- Journal of Medicinal Chemistry
- Publication Year :
- 2021
-
Abstract
- The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.
- Subjects :
- Male
Opiod receptors
NOP, MOP, Nociceptin
NOP
Receptors, Opioid, mu
Peptide
Pharmacology
01 natural sciences
Nociceptin Receptor
Opioid receptor
Drug Discovery
Receptors
Receptor
chemistry.chemical_classification
Animals
Binding Sites
Cough
Disease Models, Animal
Guinea Pigs
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Dynamics Simulation
Peptides
Receptors, Opioid
Recombinant Proteins
Structure-Activity Relationship
0303 health sciences
Chemistry
Nociceptin
Nociceptin receptor
Molecular Medicine
μ-opioid receptor
medicine.drug
Agonist
medicine.drug_class
Opioid
Article
NO
03 medical and health sciences
medicine
Settore BIO/10 - BIOCHIMICA
030304 developmental biology
MOP
Animal
0104 chemical sciences
010404 medicinal & biomolecular chemistry
mu
Disease Models
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....389d0e55aa9b9f3b2301fbd14216815d