دورية أكاديمية
أعرض في EDS

Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.

التفاصيل البيبلوغرافية
العنوان: Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.
المؤلفون: Brents LK; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, Moran JH, Prather PL
المصدر: Biochemical pharmacology [Biochem Pharmacol] 2012 Apr 01; Vol. 83 (7), pp. 952-61. Date of Electronic Publication: 2012 Jan 18.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
مواضيع طبية MeSH: Behavior, Animal/*drug effects , Cannabinoids/*pharmacology , Illicit Drugs/*metabolism , Indoles/*pharmacology , Naphthalenes/*pharmacology , Receptor, Cannabinoid, CB1/*agonists , Receptor, Cannabinoid, CB1/*antagonists & inhibitors, Animals ; Binding, Competitive ; Body Temperature/drug effects ; Brain/drug effects ; Brain/metabolism ; Cannabinoids/chemistry ; Cannabinoids/metabolism ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Drug Antagonism ; Drug Partial Agonism ; GTP-Binding Proteins/metabolism ; Hydroxylation ; Illicit Drugs/chemistry ; Illicit Drugs/pharmacology ; Indoles/chemistry ; Indoles/metabolism ; Ligands ; Male ; Mice ; Mice, Inbred Strains ; Molecular Structure ; Naphthalenes/chemistry ; Naphthalenes/metabolism ; Protein Binding ; Rats ; Rats, Sprague-Dawley
مستخلص: K2 and several similar purported "incense products" spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3-M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (K(b)∼40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.
(Copyright © 2012 Elsevier Inc. All rights reserved.)
References: Toxicol Lett. 2010 Sep 1;197(3):157-62. (PMID: 20566335)
J Pharmacol Exp Ther. 2005 Aug;314(2):868-75. (PMID: 15901805)
J Pharmacol Exp Ther. 1994 Jul;270(1):219-27. (PMID: 8035318)
Clin Biochem. 2011 Sep;44(13):1163-1165. (PMID: 21741374)
J Immunol. 2005 Mar 15;174(6):3281-9. (PMID: 15749859)
Br J Pharmacol. 2010 Sep;161(1):103-12. (PMID: 20718743)
Diabetes Obes Metab. 2010 Aug;12(8):722-30. (PMID: 20590750)
Clin Toxicol (Phila). 2011 Jun;49(5):431-3. (PMID: 21740143)
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1575-85. (PMID: 21111017)
Forensic Sci Int. 2010 Jul 15;200(1-3):141-7. (PMID: 20430547)
Forensic Sci Int. 2010 May 20;198(1-3):31-8. (PMID: 20117892)
Mol Pharmacol. 2011 Nov;80(5):859-69. (PMID: 21803969)
Pharmacol Biochem Behav. 2010 Jun;95(4):479-84. (PMID: 20347865)
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18596-601. (PMID: 19015531)
J Clin Invest. 2010 Aug;120(8):2953-66. (PMID: 20664173)
CNS Neurol Disord Drug Targets. 2010 Nov;9(5):564-73. (PMID: 20632970)
Curr Opin Psychiatry. 2006 May;19(3):233-8. (PMID: 16612207)
Curr Psychiatry Rep. 2005 Oct;7(5):360-6. (PMID: 16216154)
Drugs. 2010 Dec 24;70(18):2409-38. (PMID: 21142261)
Pharmacol Biochem Behav. 2011 Jan;97(3):537-43. (PMID: 21056053)
Horm Behav. 2010 Jun;58(1):91-9. (PMID: 19733173)
Mol Interv. 2011 Feb;11(1):36-51. (PMID: 21441120)
Drug Alcohol Depend. 2000 Aug 1;60(2):133-40. (PMID: 10940540)
Anal Chem. 2011 Aug 15;83(16):6381-8. (PMID: 21740038)
Drug Alcohol Depend. 2011 Dec 1;119(1-2):123-9. (PMID: 21724338)
PLoS One. 2011;6(7):e21917. (PMID: 21755008)
Bioorg Med Chem. 2005 Jan 3;13(1):89-112. (PMID: 15582455)
J Mass Spectrom. 2010 Oct;45(10):1186-94. (PMID: 20857386)
J Anal Toxicol. 2010 Jun;34(5):252-60. (PMID: 20529459)
Drug Test Anal. 2011 Sep;3(9):609-20. (PMID: 20872894)
Pharmacol Ther. 2011 Mar;129(3):307-20. (PMID: 21055418)
J Pharmacol Toxicol Methods. 2001 Sep-Oct;46(2):61-71. (PMID: 12481843)
Nat Neurosci. 2005 May;8(5):585-9. (PMID: 15856067)
J Addict Med. 2011 Mar;5(1):16-20. (PMID: 21359104)
J Nutr Biochem. 2010 Dec;21(12):1141-52. (PMID: 20934863)
Am J Emerg Med. 2012 Sep;30(7):1320.e5-7. (PMID: 21802885)
Drug Alcohol Depend. 2011 Sep 1;117(2-3):152-7. (PMID: 21316162)
Neurogastroenterol Motil. 2011 May;23(5):391-8. (PMID: 21481098)
Handb Exp Pharmacol. 2005;(168):1-51. (PMID: 16596770)
Bone. 2011 May 1;48(5):997-1007. (PMID: 21237298)
J Org Chem. 2008 Jun 20;73(12):4638-43. (PMID: 18494524)
Mol Psychiatry. 2012 Jun;17(6):642-9. (PMID: 21747398)
Subst Abuse Treat Prev Policy. 2011 Jul 11;6:16. (PMID: 21745369)
Physiol Behav. 2008 Mar 18;93(4-5):666-70. (PMID: 18076956)
Front Biosci (Landmark Ed). 2011 Jan 01;16(2):498-516. (PMID: 21196184)
Br J Pharmacol. 2010 Jun;160(3):585-93. (PMID: 20100276)
Chem Biodivers. 2007 Aug;4(8):1770-804. (PMID: 17712819)
Eur Arch Psychiatry Clin Neurosci. 2009 Oct;259(7):395-412. (PMID: 19568685)
Br J Pharmacol. 2005 Dec;146(7):917-26. (PMID: 16205722)
Behav Pharmacol. 2011 Sep;22(5-6):498-507. (PMID: 21836461)
Mol Pharmacol. 2000 May;57(5):1000-10. (PMID: 10779385)
J Emerg Med. 2011 Mar;40(3):296-9. (PMID: 21167669)
Schizophr Res. 2010 May;118(1-3):309-10. (PMID: 20056392)
Pharmacopsychiatry. 2010 Jun;43(4):152-3. (PMID: 20127596)
J Mass Spectrom. 2009 May;44(5):832-7. (PMID: 19189348)
J Chromatogr B Analyt Technol Biomed Life Sci. 2011 May 1;879(15-16):1126-36. (PMID: 21481654)
Best Pract Res Clin Endocrinol Metab. 2009 Feb;23(1):133-44. (PMID: 19285266)
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108. (PMID: 4202581)
Neurobiol Dis. 2010 Aug;39(2):148-55. (PMID: 20381618)
Pediatr Emerg Care. 2010 Jun;26(6):462-5. (PMID: 20531137)
Drug Alcohol Depend. 2012 Jan 1;120(1-3):238-41. (PMID: 21835562)
Eur J Pharmacol. 2011 Jun 1;659(2-3):139-45. (PMID: 21333643)
Trends Pharmacol Sci. 2009 Jan;30(1):1-7. (PMID: 19042036)
معلومات مُعتمدة: P20 RR020146 United States RR NCRR NIH HHS; 1UL1RR029884 United States RR NCRR NIH HHS; RR020146 United States RR NCRR NIH HHS; UL1 RR029884 United States RR NCRR NIH HHS; P20 RR020146-01 United States RR NCRR NIH HHS; UL1 RR029884-01 United States RR NCRR NIH HHS; P30 GM110702 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Cannabinoids)
0 (Illicit Drugs)
0 (Indoles)
0 (Ligands)
0 (Naphthalenes)
0 (Receptor, Cannabinoid, CB1)
BBX3BP2772 (JWH-073)
EC 3.6.1.- (GTP-Binding Proteins)
تواريخ الأحداث: Date Created: 20120124 Date Completed: 20120410 Latest Revision: 20240412
رمز التحديث: 20240412
مُعرف محوري في PubMed: PMC3288656
DOI: 10.1016/j.bcp.2012.01.004
PMID: 22266354
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-2968
DOI:10.1016/j.bcp.2012.01.004