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MDMB-4en-PINACA

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MDMB-4en-PINACA
Legal status
Legal status
Identifiers
  • methyl (S)-3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC20H27N3O3
Molar mass357.454 g·mol−1
3D model (JSmol)
  • O=C(N[C@@H](C(C)(C)C)C(OC)=O)C1=NN(CCCC=C)C2=C1C=CC=C2
  • InChI=1S/C20H27N3O3/c1-6-7-10-13-23-15-12-9-8-11-14(15)16(22-23)18(24)21-17(19(25)26-5)20(2,3)4/h6,8-9,11-12,17H,1,7,10,13H2,2-5H3,(H,21,24)/t17-/m1/s1
  • Key:LWOCBHBFWNGPGM-QGZVFWFLSA-N

MDMB-4en-PINACA (also incorrectly known as 5-CL-ADB-A) is an indazole-based synthetic cannabinoid that has been sold online as a designer drug.[2][3][4][5][6][7] MDMB-4en-PINACA was first identified in Europe in 2017.[8] In 2021, MDMB-4en-PINACA was the most common synthetic cannabinoid identified by the Drug Enforcement Administration in the United States.[9] MDMB-4en-PINACA differs from 5F-MDMB-PINACA due to replacement of 5-fluoropentyl with a pent-4-ene moiety (4-en).[10]

Pharmacology

It acts as a potent agonist of the CB1 receptor with an EC50 value of 2.47 nM.[11][12][13][14] MDMB-4en-PINACA has been reported to be approximately 2.5x to 3x+ (2.47 nM, 239%) stronger (by CB1 activated β-arrestin 2 recruitment) than JWH-018 (25.3 nM, 100%) with over 10x the binding affinity than JWH-018 in vitro.[15]

In a review of in vitro MDMB-4en-PINACA studies showed an EC50 of 1.88–2.47 nM, an Emax of 221–299% (compared to JWH-018), and a Ki value of 0.28nM on the CB1 receptor[16] and appears to be 7x more selective for the CB2 receptor over the CB1 receptor[17] MDMB-4en-PINACA has an in vitro half-life of approximately 10 minutes[18] but has been reported in human urine samples up to an hour after consumption, producing 14 metabolites which may have their own pharmacological activity and be used in identification of MDMB-4en-PINACA consumption.[19]

Toxicity and compositions

There has been more than 15 deaths associated with use of MDMB-4en-PINACA[20]

MDMB-4en-PINACA has been implicated in the death of a 26 year old in combination with 4F-ABUTINACA (N-(4-fluorobutyl) APINACA). The 26 year old reported headache and angina before death and was noted to have a weak pulse and death-rattle like noisy breathing after collapsing to the floor. An autopsy 5 days after death found a peripheral blood content of 7.2 ng/mL for MDMB-4en-PINACA and 9.1 ng/mL for 4F-ABUTINACA and identified brain edema, internal congestion, petechial bleeding, pleural ecchymoses, and blood fluidity.[21]

MDMB-4en-PINACA has been implicated in the death of a 35 year old. An autopsy found MDMB-4en-PINACA and one of its metabolites (MDMB-4en-PINACA 3,3-dimethylbutanoic acid) in peripheral blood at a level of 0.4 μg/L and 5.7 μg/L and 0.5 μg/L and 11.6 μg/L in cardiac blood. Urine contained 2.1 μg/L for the metabolite, and a detection below level of quantification for MDMB-4en-PINACA itself.[22]

Adulterated Cannabis products in Europe that have been laced with MDMB-4en-PINACA have contained 0.3 to 4.6 µg/mg in seized flower samples and 1.7 to 7.2 µg/mg in hash/or other extract samples.[23]

Adulterated Cannabis products in Italy that have been laced with MDMB-4en-PINACA have contained 0.4 up to 6.3 mg/g[24]

MDMB-4en-PINACA has been detected in heroin and fentanyl sold on the streets in Massachusetts.[25]

MDMB-4en-PINACA powder can range in color from white or yellow or brown or orange.

The methyl 3,3-dimethylbutanoate "head" moiety of MDMB-4en-PINACA has been implicated in higher CB1 potency but also toxicity compared to other "head" moiety groups such as the naphthene "head" moiety of JWH-018 and AM-2201 and the 2,2,3,3-tetramethylcyclopropyl (or 3-tetramethylcyclopropylmethanone) "head" moiety of UR-144 and XLR-11[26]

Sweden's public health agency suggested classifying MDMB-4en-PINACA as a hazardous substance, on December 18, 2019.[27]

In the United States, the DEA has temporarily placed MDMB-4en-PINACA into Schedule I status starting on December 12, 2023 for up to 2 years, during which it's possible the DEA could file for permanent scheduling within those 2 years. If the DEA does not file to permanent placement the temporary Schedule I order will expire on December 12, 2025.[28]

North Dakota has placed MDMB-4en-PINACA into Schedule I on 04/27/2023.[29]

See also

References

  1. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ^ Watanabe S, Vikingsson S, Åstrand A, Gréen H, Kronstrand R (December 2019). "Biotransformation of the New Synthetic Cannabinoid with an Alkene, MDMB-4en-PINACA, by Human Hepatocytes, Human Liver Microsomes, and Human Urine and Blood". The AAPS Journal. 22 (1): 13. doi:10.1208/s12248-019-0381-3. PMID 31848852. S2CID 209393242.
  3. ^ "MDMB-4en-PINACA". www.caymanchem.com.
  4. ^ Erol Ozturk Y, Yeter O (January 2021). "In Vitro Phase I Metabolism of the Recently Emerged Synthetic MDMB-4en-PINACA and Its Detection in Human Urine Samples". Journal of Analytical Toxicology. 44 (9): 976–984. doi:10.1093/jat/bkaa017. PMID 32091101.
  5. ^ Wang Y, Pan Y, Yang H, Liu J, Wurita A, Hasegawa K (July 2022). "Quantification of MDMB-4en-PINACA and ADB-BUTINACA in human hair by gas chromatography-tandem mass spectrometry". Forensic Toxicology. 40 (2): 340–348. doi:10.1007/s11419-022-00615-z. PMID 36454410. S2CID 247501663.
  6. ^ Wagmann L, Stiller RG, Fischmann S, Westphal F, Meyer MR (October 2022). "Going deeper into the toxicokinetics of synthetic cannabinoids: in vitro contribution of human carboxylesterases". Archives of Toxicology. 96 (10): 2755–2766. doi:10.1007/s00204-022-03332-z. PMC 9352624. PMID 35788413. S2CID 250281976.
  7. ^ Giorgetti A, Brunetti P, Pelotti S, Auwärter V (October 2022). "Detection of AP-237 and synthetic cannabinoids on an infused letter sent to a German prisoner". Drug Testing and Analysis. 14 (10): 1779–1784. doi:10.1002/dta.3351. PMC 9804899. PMID 35918775. S2CID 251281159.
  8. ^ https://www.who.int/docs/default-source/controlled-substances/43rd-ecdd/mdmb-4en-pinaca-review-2020.pdf?sfvrsn=5cd6e97e6
  9. ^ "Emerging Threat Report" (PDF). Drug Enforcement Administration. 2021.
  10. ^ "ANALYTICAL REPORT MDMB-PINACA N1-pentyl-4-en isomer" (PDF). www.policija.si.
  11. ^ Krotulski AJ, Cannaert A, Stove C, Logan BK (February 2021). "The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent-4en and but-3en analogues including MDMB-4en-PINACA". Drug Testing and Analysis. 13 (2): 427–438. doi:10.1002/dta.2935. PMID 32997377. S2CID 222148050.
  12. ^ Cannaert A, Sparkes E, Pike E, Luo JL, Fang A, Kevin RC, et al. (December 2020). "Synthesis and in Vitro Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA". ACS Chemical Neuroscience. 11 (24): 4434–4446. doi:10.1021/acschemneuro.0c00644. PMID 33253529. S2CID 227246346.
  13. ^ Pike E, Grafinger KE, Cannaert A, Ametovski A, Luo JL, Sparkes E, et al. (July 2021). "Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays: Part I-Synthesis, analytical characterization, and binding affinity for human CB1 receptors". Drug Testing and Analysis. 13 (7): 1383–1401. doi:10.1002/dta.3037. PMID 33787091.
  14. ^ Grafinger KE, Cannaert A, Ametovski A, Sparkes E, Cairns E, Banister SD, et al. (July 2021). "Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays-Part II: Structure activity relationship assessment via a β-arrestin recruitment assay". Drug Testing and Analysis. 13 (7): 1402–1411. doi:10.1002/dta.3035. PMID 33769699.
  15. ^ Krotulski, Alex J.; Cannaert, Annelies; Stove, Christophe; Logan, Barry K. (2021). "The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent-4en and but-3en analogues including MDMB-4en-PINACA". Drug Testing and Analysis. 13 (2): 427–438. doi:10.1002/dta.2935. PMID 32997377. S2CID 222148050.
  16. ^ Simon, Gábor; Kuzma, Mónika; Mayer, Mátyás; Petrus, Karola; Tóth, Dénes (2023). "Fatal Overdose with the Cannabinoid Receptor Agonists MDMB-4en-PINACA and 4F-ABUTINACA: A Case Report and Review of the Literature". Toxics. 11 (8): 673. doi:10.3390/toxics11080673. PMC 10458319. PMID 37624178.
  17. ^ Marusich, J. A.; Gamage, T. F.; Zhang, Y.; Akinfiresoye, L. R.; Wiley, J. L. (2022). "In vitro and in vivo pharmacology of nine novel synthetic cannabinoid receptor agonists". Pharmacology, Biochemistry, and Behavior. 220. doi:10.1016/j.pbb.2022.173467. PMC 9837865. PMID 36154844.
  18. ^ https://www.emcdda.europa.eu/system/files/publications/14035/Synthetic-cannabinoids-in-Europe-EMCDDA-technical-report.pdf
  19. ^ Erol Ozturk, Y.; Yeter, O. (2021). "In Vitro Phase I Metabolism of the Recently Emerged Synthetic MDMB-4en-PINACA and Its Detection in Human Urine Samples". Journal of Analytical Toxicology. 44 (9): 976–984. doi:10.1093/jat/bkaa017. PMID 32091101.
  20. ^ https://www.drugsandalcohol.ie/33912/1/emcdda-RAR-MDMB-4en-PINACA_NEW.pdf
  21. ^ Simon, Gábor; Kuzma, Mónika; Mayer, Mátyás; Petrus, Karola; Tóth, Dénes (2023). "Fatal Overdose with the Cannabinoid Receptor Agonists MDMB-4en-PINACA and 4F-ABUTINACA: A Case Report and Review of the Literature". Toxics. 11 (8): 673. doi:10.3390/toxics11080673. PMC 10458319. PMID 37624178.
  22. ^ Arnault, Audrey; Meiries, Sébastien; Mauras, Michel; Navarette, Claudie; Berland, Emilie; Soumireu-Lartigue, Stéphane (2022). "Dramatical outcome following the consumption of a joint containing the synthetic cannabinoid MDMB-4en-PINACA: A case report". Toxicologie Analytique et Clinique. 34 (3): S93. doi:10.1016/j.toxac.2022.06.142.
  23. ^ Monti, Manuela Carla; Zeugin, Jill; Koch, Konrad; Milenkovic, Natasa; Scheurer, Eva; Mercer-Chalmers-Bender, Katja (2022). "Adulteration of low-delta-9-tetrahydrocannabinol products with synthetic cannabinoids: Results from drug checking services". Drug Testing and Analysis. 14 (6): 1026–1039. doi:10.1002/dta.3220. PMC 9305195.
  24. ^ Gerace, E.; Seganti, F.; Di Corcia, D.; Vincenti, M.; Salomone, A. (2022). "GC-MS Identification and Quantification of the Synthetic Cannabinoid MDMB-4en- PINACA in Cannabis-derived Material Seized in the Turin Metropolitan Area (Italy)". Current Pharmaceutical Design. 28 (32): 2618–2621. doi:10.2174/1381612828666220603142859. PMID 35658890. S2CID 249396142.
  25. ^ https://heller.brandeis.edu/opioid-policy/pdfs/mdmb-4en-pinaca-pd-one-pager_v2_3.8.21.pdf
  26. ^ Yano, Hideaki; Chitsazi, Rezvan; Lucaj, Christopher; Tran, Phuong; Hoffman, Alexander F.; Baumann, Michael H.; Lupica, Carl R.; Shi, Lei (2023). "Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor". ACS Chemical Neuroscience. 14 (21): 3928–3940. doi:10.1021/acschemneuro.3c00530. PMC 10623572. PMID 37847546.
  27. ^ "Tjugotre ämnen föreslås klassas som narkotika eller hälsofarlig vara" [Twenty-three substances are proposed to be classified as narcotics or health hazards]. Folkhälsomyndigheten [The Public Health Authority] (in Swedish). 18 December 2019. Archived from the original on 19 December 2019.
  28. ^ "Federal Register :: Request Access".
  29. ^ "AN ACT to amend and reenact sections 19-03.1-05, 19-03.1-11, and 19-03.1-13 of the North Dakota Century Code, relating to the scheduling of controlled substances; and to declare an emergency" (PDF). Sixty-eighth Legislative Assembly of North Dakota in Regular Session. 3 January 2023.
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