Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity.
Adamantane
/ analogs & derivatives
Animals
Cannabinoid Receptor Antagonists
/ pharmacology
Cytochrome P-450 CYP2D6
/ genetics
Cytochrome P-450 CYP3A
/ genetics
Female
Humans
Indazoles
/ metabolism
Male
Mice
Mice, Inbred C57BL
Microsomes, Liver
/ drug effects
Oxidation-Reduction
/ drug effects
Polymorphism, Genetic
Protein Binding
Receptor, Cannabinoid, CB1
/ agonists
Recombinant Proteins
/ metabolism
Rimonabant
/ pharmacology
Sex Factors
Adverse effects
Cannabinoid receptors
HPLC
MS
Metabolism
P450 polymorphism
Synthetic cannabinoids
Journal
Pharmacology, biochemistry, and behavior
ISSN: 1873-5177
Titre abrégé: Pharmacol Biochem Behav
Pays: United States
ID NLM: 0367050
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
06
01
2020
accepted:
11
05
2020
pubmed:
16
5
2020
medline:
9
2
2021
entrez:
16
5
2020
Statut:
ppublish
Résumé
AKB48 and its fluorinated derivative 5F-AKB48 are synthetic cannabinoids (SCs) which have caused hospitalizations and deaths in human users. Abuse of SCs is dangerous because users may mistake them for natural cannabis, which is generally considered to be unlikely to elicit adverse effects. The present studies were designed to investigate the in vitro oxidative metabolism of 5F-AKB48 by human microsomal fractions from different organs and sexes as well as recombinant human cytochrome P450s (P450s). Mass spectrometry data tentatively provides evidence for the existence of mono-, di-, and trihydroxylated metabolites in a successive metabolism. Experiments utilizing P450s revealed that the most active enzymes (CYP2D6, CYP2J2, CYP3A4, and CYP3A5) effectively produced mono- and dihydroxylated metabolites, while CYP3A4/5 also produced significant amounts of the trihydroxylated metabolite. Moreover, although the affinity and potency of Phase I metabolite 4OH-5F-AKB48 is reduced when compared to that of the parent drug, this metabolite nevertheless retains similar high affinity for CB1 receptors, and greater efficacy for G protein activation, when compared to THC. Finally, 5F-AKB48 produced time- and dose-dependent cannabimimetic effects in mice which were more potent, but shorter acting, than those of Δ
Identifiants
pubmed: 32413436
pii: S0091-3057(20)30013-7
doi: 10.1016/j.pbb.2020.172949
pmc: PMC7415729
mid: NIHMS1598042
pii:
doi:
Substances chimiques
Cannabinoid Receptor Antagonists
0
Indazoles
0
N-(1-adamantyl)-1-pentylindazole-3-carboxamide
0
Receptor, Cannabinoid, CB1
0
Recombinant Proteins
0
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Adamantane
PJY633525U
Rimonabant
RML78EN3XE
N-(1-adamantyl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide
TX64ZY5P0R
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
172949Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM103429
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA039143
Pays : United States
Organisme : NIDA NIH HHS
ID : T32 DA022981
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no conflict of interest.
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