MDMB-4en-PINACA

Last updated
MDMB-4en-PINACA
MDMB-4en-PINACA.svg
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
Formula C20H27N3O3
Molar mass 357.454 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]

Contents

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

Related Research Articles

<span class="mw-page-title-main">MN-18</span> Chemical compound

MN 18 is an indazole-based synthetic cannabinoid that is an agonist for the cannabinoid receptors, with Ki values of 45.72 nM at CB1 and 11.098 nM at CB2 and EC50 values of 2.028 nM at CB1 and 1.233 nM at CB2, and has been sold online as a designer drug. It is the indazole core analogue of NNE1. Given the known metabolic liberation (and presence as an impurity) of amantadine in the related compound APINACA, it is suspected that metabolic hydrolysis of the amide group of MN-18 may release 1-naphthylamine, a known carcinogen. MN-18 metabolism has been described in literature.

<span class="mw-page-title-main">AB-CHMINACA</span> Chemical compound

AB-CHMINACA is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor (Ki = 0.78 nM) and CB2 receptor (Ki = 0.45 nM) and fully substitutes for Δ9-THC in rat discrimination studies, while being 16x more potent. Continuing the trend seen in other cannabinoids of this generation, such as AB-FUBINACA and AB-PINACA, it contains a valine amino acid amide residue as part of its structure, where older cannabinoids contained a naphthyl or adamantane residue.

<span class="mw-page-title-main">5F-AMB</span> Chemical compound

5F-AMB (also known as 5F-MMB-PINACA and 5F-AMB-PINACA) is an indazole-based synthetic cannabinoid from the indazole-3-carboxamide family, which has been used as an active ingredient in synthetic cannabis products. It was first identified in Japan in early 2014. Although only very little pharmacological information about 5F-AMB itself exists, its 4-cyanobutyl analogue (instead of 5-fluoropentyl) has been reported to be a potent agonist for the CB1 receptor (KI = 0.7 nM).

<span class="mw-page-title-main">MDMB-CHMICA</span> Chemical compound

MDMB-CHMICA is an indole-based synthetic cannabinoid that is a potent agonist of the CB1 receptor and has been sold online as a designer drug. While MDMB-CHMICA was initially sold under the name "MMB-CHMINACA", the compound corresponding to this code name (i.e. the isopropyl instead of t-butyl analogue of MDMB-CHMINACA) has been identified on the designer drug market in 2015 as AMB-CHMINACA.

<span class="mw-page-title-main">MDMB-FUBINACA</span> Chemical compound

MDMB-FUBINACA (also known as MDMB(N)-Bz-F and FUB-MDMB) is an indazole-based synthetic cannabinoid that is a potent agonist for the cannabinoid receptors, with Ki values of 1.14 nM at CB1 and 0.1228 nM at CB2 and EC50 values of 0.2668 nM at CB1 and 0.1411 nM at CB2, and has been sold online as a designer drug. Its benzyl analogue (instead of 4-fluorobenzyl) has been reported to be a potent agonist for the CB1 receptor (Ki = 0.14 nM, EC50 = 2.42 nM). The structure of MDMB-FUBINACA contains the amino acid, 3-methylvaline or tert-leucine methyl ester.

<span class="mw-page-title-main">APP-FUBINACA</span> Chemical compound

APP-FUBINACA is an indazole-based synthetic cannabinoid that has been sold online as a designer drug. Pharmacological testing showed APP-FUBINACA to have only moderate affinity for the CB1 receptor, with a Ki of 708 nM, while its EC50 was not tested. It contains a phenylalanine amino acid residue in its structure.

<span class="mw-page-title-main">AMB-FUBINACA</span> Chemical compound

AMB-FUBINACA (also known as FUB-AMB and MMB-FUBINACA) is an indazole-based synthetic cannabinoid that is a potent agonist for the cannabinoid receptors, with Ki values of 10.04 nM at CB1 and 0.786 nM at CB2 and EC50 values of 0.5433 nM at CB1 and 0.1278 nM at CB2, and has been sold online as a designer drug. It was originally developed by Pfizer which described the compound in a patent in 2009, but was later abandoned and never tested on humans. AMB-FUBINACA was the most common synthetic cannabinoid identified in drug seizures by the Drug Enforcement Administration in 2017 and the first half of 2018.

<span class="mw-page-title-main">FUB-APINACA</span> Chemical compound

FUB-APINACA (also known as A-FUBINACA according to the EMCCDA framework for naming synthetic cannabinoids and FUB-AKB48) is an indazole-based synthetic cannabinoid that is presumed to be a potent agonist of the CB1 receptor and has been sold online as a designer drug. It is an analog of APINACA and 5F-APINACA where the pentyl chain has been replaced with fluorobenzyl.

<span class="mw-page-title-main">5F-AB-FUPPYCA</span> Chemical compound

5F-AB-FUPPYCA (also known as AZ-037) is a pyrazole-based synthetic cannabinoid that is presumed to be an agonist of the CB1 receptor and has been sold online as a designer drug. It was first detected by the EMCDDA as part of a seizure of 540 g white powder in France in February 2015.

<span class="mw-page-title-main">CUMYL-4CN-BINACA</span> Chemical compound

CUMYL-4CN-BINACA (also known as CUMYL-CYBINACA or SGT-78) is an indazole-3-carboxamide based synthetic cannabinoid that has been sold online as a designer drug. It is a potent agonist for cannabinoid receptors CB1 and CB2, with in vitro EC50 values of 0.58 nM and 6.12 nM, respectively. In mice, CUMYL-4CN-BINACA produces hypothermic and pro-convulsant effects via the CB1 receptor, and anecdotal reports suggest it has an active dose of around 0.1 mg in humans.

<span class="mw-page-title-main">5F-CUMYL-P7AICA</span> Chemical compound

5F-CUMYL-P7AICA is a pyrrolo[2,3-b]pyridine-3-carboxamide based synthetic cannabinoid that has been sold as a designer drug. It was first identified by the EMCDDA in February 2015.

<span class="mw-page-title-main">4F-MDMB-BINACA</span> Chemical compound

4F-MDMB-BINACA (also known as 4F-MDMB-BUTINACA or 4F-ADB) is an indazole-based synthetic cannabinoid from the indazole-3-carboxamide family. It has been used as an active ingredient in synthetic cannabis products and sold as a designer drug since late 2018. 4F-MDMB-BINACA is an agonist of the CB1 receptor (EC50 = 7.39 nM), though it is unclear whether it is selective for this target. In December 2019, the UNODC announced scheduling recommendations placing 4F-MDMB-BINACA into Schedule II throughout the world.

<span class="mw-page-title-main">CUMYL-CBMICA</span> Chemical compound

CUMYL-CBMICA (SGT-280) is an indole-3-carboxamide based synthetic cannabinoid receptor agonist which has been sold as a designer drug, first being identified in Germany in August 2019. Since the structure fell outside the German drug analogue law provisions at the time, an amendment was made to the law to expand the relevant definition, which came into effect in April 2020. It has been shown to act as a CB1 receptor agonist with an EC50 of 62.9nM.

<span class="mw-page-title-main">ADB-BINACA</span> Chemical compound

ADB-BINACA is a cannabinoid designer drug that has been found as an ingredient in some synthetic cannabis products. It was originally developed by Pfizer as a potential analgesic, and is a potent agonist of the CB1 receptor with a binding affinity (Ki) of 0.33 nM and an EC50 of 14.7 nM.

<span class="mw-page-title-main">ADB-BUTINACA</span> Chemical compound

ADB-BUTINACA is a synthetic cannabinoid compound which has been sold as a designer drug. It is a potent CB1 agonist, with a binding affinity of 0.29nM for CB1 and 0.91nM for CB2, and an EC50 of 6.36 nM for CB1.

<span class="mw-page-title-main">ADB-HEXINACA</span> Chemical compound

ADB-HEXINACA is a cannabinoid designer drug that has been found as an ingredient in some synthetic cannabis products, first appearing in early 2021. It is a longer chain homologue of previously encountered synthetic cannabinoid compounds such as ADB-BUTINACA and ADB-PINACA.

<span class="mw-page-title-main">ADB-4en-PINACA</span> Chemical compound

ADB-4en-PINACA is a cannabinoid designer drug that has been found as an ingredient in some synthetic cannabis products, first appearing in early 2021. It is a reasonably potent cannabinoid agonist in vitro but has not been so widely sold as related compounds such as ADB-PINACA and MDMB-4en-PINACA.

<span class="mw-page-title-main">MDMB-5Br-INACA</span> Chemical compound

MDMB-5Br-INACA is an indazole-3-carboxamide derivative which has been sold as a designer drug. Surprisingly it appears to produce psychoactive activity despite the lack of a "tail" group at the indazole 1-position, but is of relatively low potency and has been encountered being misrepresented as other illicit drugs such as MDMA.

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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