Metabolic Profiling of a CB2 Agonist, AM9338, Using LC-MS and Microcoil-NMR: Identification of a Novel Dihydroxy Adamantyl Metabolite.
CB2 agonist
CYP3A4 metabolism
LC-MS
adamantyl metabolism
cannabinoid metabolism
di-hydroxyl adamantyl metabolite
metabolite identification
micro-coil NMR
Journal
Frontiers in pharmacology
ISSN: 1663-9812
Titre abrégé: Front Pharmacol
Pays: Switzerland
ID NLM: 101548923
Informations de publication
Date de publication:
2020
2020
Historique:
received:
24
06
2020
accepted:
24
08
2020
entrez:
26
10
2020
pubmed:
27
10
2020
medline:
27
10
2020
Statut:
epublish
Résumé
Adamantyl groups are key structural subunit commonly used in many marketed drugs targeting diseases ranging from viral infections to neurological disorders. The metabolic disposition of adamantyl compounds has been mostly studied using LC-MS based approaches. However, metabolite quantities isolated from biological preparations are often insufficient for unambiguous structural characterization by NMR. In this work, we utilized microcoil NMR in conjunction with LC-MS to characterize liver microsomal metabolites of an adamantyl based CB2 agonist AM9338, 1-(3-(1H-1,2,3-triazol-1-yl) propyl)-N-(adamantan-1-yl)-1H-indazole-3-carboxamide, a candidate compound for potential multiple sclerosis treatment. We have identified a total of 9 oxidative metabolites of AM9338 whereas mono- or di-hydroxylation of the adamantyl moiety is the primary metabolic pathway. While it is generally believed that the tertiary adamantyl carbons are the preferred sites of CYP450 oxidation, both the mono- and di-hydroxyl metabolites of AM9338 show that the primary oxidative sites are located on the secondary adamantyl carbons. To our knowledge this di-hydroxylated metabolite is a novel adamantyl metabolite that has not been reported before. Further, the stereochemistry of both mono- and di-hydroxyl adamantyl metabolites has been determined using NOE correlations. Furthermore, docking of AM9338 into the CYP3A4 metabolic enzyme corroborates with our experimental findings, and the modelling results also provide a possible mechanism for the unusual susceptibility of adamantyl secondary carbons to metabolic oxidations. The novel dihydroxylated AM9338 metabolite identified in this study, along with the previously known adamantyl metabolites, gives a more complete picture of the metabolic disposition for adamantyl compounds.
Identifiants
pubmed: 33101030
doi: 10.3389/fphar.2020.575691
pmc: PMC7556269
doi:
Types de publication
Journal Article
Langues
eng
Pagination
575691Subventions
Organisme : NIDA NIH HHS
ID : R21 DA032020
Pays : United States
Organisme : NIDA NIH HHS
ID : R33 DA032020
Pays : United States
Organisme : NIDA NIH HHS
ID : R37 DA003801
Pays : United States
Organisme : NIDA NIH HHS
ID : P01 DA009158
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA003801
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020 Honrao, Ma, Kulkarni, Joshi, Malamas, Zvonok, Wood, Strand, Guo and Makriyannis.
Références
J Med Chem. 2005 Jul 14;48(14):4576-85
pubmed: 15999995
J Comb Chem. 2005 Jan-Feb;7(1):14-20
pubmed: 15638474
J Anal Toxicol. 2015 Jul-Aug;39(6):426-35
pubmed: 25957385
Bioorg Med Chem. 2005 Mar 1;13(5):1749-61
pubmed: 15698792
Nature. 2008 Jan 31;451(7178):596-9
pubmed: 18235504
Cell. 2019 Jan 24;176(3):459-467.e13
pubmed: 30639103
Neurosci Lett. 2015 May 19;595:1-6
pubmed: 25849525
Best Pract Res Clin Endocrinol Metab. 2009 Aug;23(4):487-98
pubmed: 19748066
AAPS J. 2015 Sep;17(5):1237-45
pubmed: 26002511
AAPS J. 2013 Oct;15(4):1091-8
pubmed: 23913126
Anal Chem. 2008 Nov 1;80(21):8045-54
pubmed: 18834150
J Anal Toxicol. 2016 Apr;40(3):173-86
pubmed: 26792810
Anal Chem. 2004 May 15;76(10):2966-74
pubmed: 15144211
Skinmed. 2005 May-Jun;4(3):138-46
pubmed: 15891249
N Engl J Med. 2003 Apr 3;348(14):1333-41
pubmed: 12672860
Xenobiotica. 2019 May;49(5):577-583
pubmed: 29790809
Methods Mol Biol. 2008;426:447-58
pubmed: 18542883
Chem Res Toxicol. 2013 Oct 21;26(10):1424-9
pubmed: 24028148
J Chem Theory Comput. 2016 Jan 12;12(1):281-96
pubmed: 26584231
J Med Chem. 2017 Jun 22;60(12):4932-4948
pubmed: 28537398
J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Apr 15;1083:189-197
pubmed: 29549742
J Med Chem. 2010 Aug 12;53(15):5656-66
pubmed: 20593789
Bioorg Chem. 2018 Feb;76:510-527
pubmed: 29310082
Expert Opin Ther Targets. 2008 Feb;12(2):185-95
pubmed: 18208367
Drug Metab Rev. 2014 Feb;46(1):72-85
pubmed: 24063277
Drug Test Anal. 2015 Mar;7(3):187-98
pubmed: 24827428
Cochrane Database Syst Rev. 2003;(1):CD003468
pubmed: 12535476
Mol Cell Biochem. 2002 Oct;239(1-2):45-54
pubmed: 12479567
J Mol Neurosci. 2001 Apr-Jun;16(2-3):133-42; discussion 151-7
pubmed: 11478368
Curr Med Chem. 2016;23(29):3245-3266
pubmed: 27222266
Molecules. 2017 Jun 17;22(6):
pubmed: 28629119
Anal Methods. 2012 Jan 1;4(5):1315-1325
pubmed: 22707983
Anal Chem. 1998 Feb 1;70(3):645-50
pubmed: 9470492
J Med Chem. 2008 Aug 28;51(16):5075-84
pubmed: 18680276
Bioorg Med Chem Lett. 2013 Mar 1;23(5):1177-81
pubmed: 23380378
Curr Opin Chem Biol. 2002 Oct;6(5):711-6
pubmed: 12413558
Curr Med Chem. 2010;17(26):2967-78
pubmed: 20858176
J Med Chem. 2016 May 12;59(9):4210-20
pubmed: 26371436
J Med Chem. 2007 Jan 11;50(1):149-64
pubmed: 17201418
ACS Chem Neurosci. 2013 Jul 17;4(7):1081-92
pubmed: 23551277
Chem Res Toxicol. 2009 Feb;22(2):299-310
pubmed: 18980340
Bioorg Chem. 2011 Aug;39(4):151-8
pubmed: 21864882
Cochrane Database Syst Rev. 2004;(3):CD001169
pubmed: 15266442
Neuropharmacology. 2009 Apr;56(5):866-75
pubmed: 19371579
J Proteome Res. 2017 Jul 7;16(7):2419-2428
pubmed: 28374590
Br J Pharmacol. 2008 Jan;153(2):216-25
pubmed: 17891163
Chem Rev. 2013 May 8;113(5):3516-604
pubmed: 23432396
Angew Chem Int Ed Engl. 2006 Nov 6;45(43):7122-31
pubmed: 16991159