Pharmacological characterization of 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[(3'-fluoro-4'-pyridyl)acetamido]morphinan (NFP) as a dual selective MOR/KOR ligand with potential applications in treating opioid use disorder.
Analgesics, Opioid
/ pharmacology
Animals
Biological Transport
CHO Cells
Caco-2 Cells
Calcium
/ metabolism
Cell Line, Tumor
Cricetulus
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
/ pharmacology
Humans
Ligands
Male
Mice, Inbred C57BL
Morphinans
/ pharmacology
Narcotic Antagonists
/ pharmacology
Opioid-Related Disorders
/ drug therapy
Receptors, Opioid, kappa
/ agonists
Receptors, Opioid, mu
/ agonists
Desensitization
Down regulation
Drug abuse and addiction
Dual-selective opioid antagonist
NFP
Opioid use disorder
Journal
European journal of pharmacology
ISSN: 1879-0712
Titre abrégé: Eur J Pharmacol
Pays: Netherlands
ID NLM: 1254354
Informations de publication
Date de publication:
15 Dec 2019
15 Dec 2019
Historique:
received:
24
05
2019
revised:
07
11
2019
accepted:
14
11
2019
pubmed:
20
11
2019
medline:
21
5
2020
entrez:
20
11
2019
Statut:
ppublish
Résumé
For thousands of years opioids have been the first-line treatment option for pain management. However, the tolerance and addiction potential of opioids limit their applications in clinic. NFP, a MOR/KOR dual-selective opioid antagonist, was identified as a ligand that significantly antagonized the antinociceptive effects of morphine with lesser withdrawal effects than naloxone at similar doses. To validate the potential application of NFP in opioid addiction treatment, a series of in vitro and in vivo assays were conducted to further characterize its pharmacological profile. In calcium mobilization assays and MOR internalization studies, NFP showed the apparent capacity to antagonize DAMGO-induced calcium flux and etorphine-induced MOR internalization. In contrast to the opioid agonists DAMGO and morphine, cells pretreated with NFP did not show apparent desensitization and down regulation of the MOR. Though in vitro bidirectional transport studies showed that NFP might be a P-gp substrate, in warm-water tail-withdrawal assays it was able to antagonize the antinociceptive effects of morphine indicating its potential central nervous system activity. Overall these results suggest that NFP is a promising dual selective opioid antagonist that may have the potential to be used therapeutically in opioid use disorder treatment.
Identifiants
pubmed: 31743739
pii: S0014-2999(19)30764-2
doi: 10.1016/j.ejphar.2019.172812
pmc: PMC6914219
mid: NIHMS1545370
pii:
doi:
Substances chimiques
Analgesics, Opioid
0
Ligands
0
Morphinans
0
Narcotic Antagonists
0
Receptors, Opioid, kappa
0
Receptors, Opioid, mu
0
Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
100929-53-1
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
172812Subventions
Organisme : NIDA NIH HHS
ID : P30 DA013429
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA024022
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA041359
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA044855
Pays : United States
Organisme : NIDA NIH HHS
ID : R21 DA045274
Pays : United States
Organisme : NIDA NIH HHS
ID : UG3 DA050311
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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