Research Progress in Pharmacodynamics and Pharmacokinetics of Indole and Indazole-3-Carboxamide Synthetic Cannabinoids

doi:10.12116/j.issn.1004-5619.2024.340301

Abstract

Abstract:

Since the emergence of indole and indazole-3-carboxamide synthetic cannabinoids, they have caused serious public health and social problems. These substances exhibit considerable structural diversity and undergo extensive and rapid metabolism both in vivo and in vitro. Their parent compounds cannot be detected in biological samples, while the precise mechanisms responsible for their harmful effects are still not fully understood. These characteristics present significant challenges for toxicological screening and forensic toxicology case analysis. Given the similar structural and physicochemical properties of indole and indazole-3-carboxamide synthetic cannabinoids, this review conducts a literature survey of recent research on these substances based on structural considerations, and summarizes their pharmacodynamics, pharmacokinetics, and other relevant research findings, with the aim of providing a reference for forensic identification and the regulation of these substances.

Key words: forensic medicine, toxicological analysis, new psychoactive substance, indole and indazole-3-carboxamide synthetic cannabinoids, pharmacodynamics, pharmacokinetics, review

CLC Number:

Xinyi Yan, Peng Xu, Bin Di. Research Progress in Pharmacodynamics and Pharmacokinetics of Indole and Indazole-3-Carboxamide Synthetic Cannabinoids[J]. Journal of Forensic Medicine, 2026, 42(4): 366-373.

Add to citation manager EndNote|Ris|BibTeX

URL: http://www.fyxzz.cn/EN/10.12116/j.issn.1004-5619.2024.340301

http://www.fyxzz.cn/EN/Y2026/V42/I4/366

Figures/Tables 2

References 63

[1]	Lea Houston M， Morgan J， Kelso C. Narrative review of the pharmacodynamics， pharmacokinetics， and toxicities of illicit synthetic cannabinoid receptor agonists[J]. Mini Rev Med Chem，2024，24（1）：92-109. doi：10.2174/1389557523666230515163107 .
[2]	Castaneto M S， Gorelick D A， Desrosiers N A， et al. Synthetic cannabinoids： Epidemiology， pharmacodynamics， and clinical implications[J]. Drug Alcohol Depend，2014，144：12-41. doi：10.1016/j.drugal cdep.2014.08.005 .
[3]	Auwärter V， Dresen S， Weinmann W， et al. ‘Spice’ and other herbal blends： Harmless incense or cannabinoid designer drugs?[J]. J Mass Spectrom，2009，44（5）：832-837. doi：10.1002/jms.1558 .
[4]	Giorgetti A， Busardò F P， Tittarelli R， et al. Post-mortem toxicology： A systematic review of death cases involving synthetic cannabinoid receptor agonists[J]. Front Psychiatry，2020，11：464. doi：10.3389/fpsyt.2020.00464 .
[5]	整类列管合成大麻素类物质7月1日起施行，我国成为全球首个整类列管合成大麻素类物质的国家[EB/OL]. （2021-05-12）[2024-02-20]. .
	The class-wide control of synthetic cannabinoids will take effect on July 1， making China the first country in the world to place synthetic cannabinoids under class-wide control[EB/OL]. （2021-05-12）[2024-02-20].
	content.html.
[6]	杨哲，吕建霞，吴一荻，等. 超高效液相色谱法同时测定电子烟油中的5种吲哚/吲唑酰胺类合成大麻素[J].色谱，2023，41（7）：602-609. doi：10.3724/SP.J.1123.2022.10014 .
	Yang Z， Lü J X， Wu Y D， et al. Simultaneous determination of five indole/indazole amide-based synthetic cannabinoids in electronic cigarette oil by ultra performance liquid chromatography[J]. Sepu，2023，41（7）：602-609.
[7]	Gandhi A S， Zhu M S， Pang S K， et al. First characterization of AKB-48 metabolism， a novel synthetic cannabinoid， using human hepatocytes and high-resolution mass spectrometry[J]. AAPS J，2013，15（4）：1091-1098. doi：10.1208/s12248-013-9516-0 .
[8]	Gatch M B， Forster M J. Δ⁹-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market[J]. Behav Pharmacol，2015，26（5）：460-468. doi：10.1097/FBP.0000000000000150 .
[9]	Banister S D， Longworth M， Kevin R， et al. Pharmacology of valinate and tert-leucinate synthetic cannabinoids 5F-AMBICA， 5F-AMB， 5F-ADB， AMB-FUBINACA， MDMB-FUBINACA， MDMB-CHMICA， and their analogues[J]. ACS Chem Neurosci，2016，7（9）：1241-1254. doi：10.1021/acschem neuro.6b00137 .
[10]	Yano H， Chitsazi R， Lucaj C， et al. Subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor[J]. ACS Chem Neurosci，2023，14（21）：3928-3940. doi：10.1021/acschemneuro.3c00530 .
[11]	Pike E， Grafinger K E， Cannaert A， et al. 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[J]. Drug Test Anal，2021，13（7）：1383-1401. doi：10.1002/dta.3037 .
[12]	Lobato-Freitas C， Brito-da-Costa A M， Dinis-Oliveira R J， et al. Overview of synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA： Clinical， analytical， and forensic implications[J]. Pharmaceuticals （Basel），2021，14（3）：186. doi：10.3390/ph14030186 .
[13]	Fabregat-Safont D， Mardal M， Noble C， et al. Comprehensive investigation on synthetic cannabinoids： Metabolic behavior and potency testing， using 5F-APP-PICA and AMB-FUBINACA as model compounds[J]. Drug Test Anal，2019，11（9）：1358-1368. doi：10.1002/dta.2659 .
[14]	Wouters E， Mogler L， Cannaert A， et al. Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L-valine or L-tert-leucine[J]. Drug Test Anal，2019，11（8）：1183-1191. doi：10.1002/dta.2607 .
[15]	Dvorácskó S， Körmöczi T， Sija É， et al. Focusing on the 5F-MDMB-PICA， 4F-MDMB-BICA synthetic cannabinoids and their primary metabolites in analytical and pharmacological aspects[J]. Toxicol Appl Pharmacol，2023，470：116548. doi：10.1016/j.taap.2023.116548 .
[16]	Longworth M， Connor M， Banister S D， et al. Synthesis and pharmacological profiling of the metabolites of synthetic cannabinoid drugs APICA， STS-135， ADB-PINACA， and 5F-ADB-PINACA[J]. ACS Chem Neurosci，2017，8（8）：1673-1680. doi：10.1021/acschemneuro.7b00116 .
[17]	Darke S， Duflou J， Farrell M， et al. Characteristics and circumstances of synthetic cannabinoid-related death[J]. Clin Toxicol （Phila），2020，58（5）：368-374. doi：10.1080/15563650.2019.1647344 .
[18]	Lam R P K， Tang M H Y， Leung S C， et al. Supraventricular tachycardia and acute confusion following ingestion of e-cigarette fluid containing AB-FUBINACA and ADB-FUBINACA： A case report with quantitative analysis of serum drug concentrations[J]. Clin Toxicol （Phila），2017，55（7）：662-667. doi：10.1080/15563650.2017.1307385 .
[19]	Lurie Y， Nadir Y， Hoffman R， et al. An outbreak of severe coagulopathy in northern Israel among users of illicit synthetic cannabinoids adulterated with brodifacoum[J]. Clin Toxicol （Phila），2023，61（6）：429-435. doi：10.1080/15563650.2023.2215402 .
[20]	Peruch M， Addobbati R， Padovano M， et al. Identification of 5F-cumyl-PINACA， a synthetic cannabinoid， in the herbal material used for recreational purposes in the province of Trieste： Public health implications[J]. Curr Pharm Biotechnol，2023，24（6）：758-765. doi：10.2174/1389201023666220915092609 .
[21]	European Monitoring Centre for Drugs and Drug Addiction. Perspectives on drugs： Synthetic cannabinoids in Europe[R/OL]. （2017-06-06）[2024-02-20]. .
[22]	Brandon A M， Antonides L H， Riley J， et al. A systematic study of the in vitro pharmacokinetics and estimated human in vivo clearance of indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists detected on the illicit drug market[J]. Molecules，2021，26（5）：1396. doi：10.3390/molecules 26051396 .
[23]	Grafinger K E， Cannaert A， Ametovski A， et al. 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[J]. Drug Test Anal，2021，13（7）：1402-1411. doi：10.1002/ dta.3035 .
[24]	Ametovski A， Macdonald C， Manning J J， et al. Exploring stereochemical and conformational requirements at cannabinoid receptors for synthetic cannabinoids related to SDB-006， 5F-SDB-006， CUMYL-PICA， and 5F-CUMYL-PICA[J]. ACS Chem Neurosci，2020，11（21）：3672-3682. doi：10.1021/acschem neuro.0c00591 .
[25]	Cannaert A， Sparkes E， Pike E， et al. 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[J]. ACS Chem Neurosci，2020，11（24）：4434-4446. doi：10.1021/acschemneuro.0c00644 .
[26]	Green H， Åstrand A， Persson M， et al. CB1 activity of three classes of synthetic cannabinoids and their metabolites — The tail needs to know what the head is doing[J]. Toxicol Anal Clin，2022，34（S3）：S75. doi：10.1016/j.toxac.2022.06.104 .
[27]	Antonides L H， Cannaert A， Norman C， et al. Shape matters： The application of activity-based in vitro bioassays and chiral profiling to the pharmacological evaluation of synthetic cannabinoid receptor agonists in drug-infused papers seized in prisons[J]. Drug Test Anal，2021，13（3）：628-643. doi：10.1002/dta.2965 .
[28]	Antonides L H， Cannaert A， Norman C， et al. Enantiospecific synthesis， chiral separation， and biological activity of four indazole-3-carboxamide-type synthetic cannabinoid receptor agonists and their detection in seized drug samples[J]. Front Chem，2019，7：321. doi：10.3389/fchem.2019.00321 .
[29]	Doi T， Asada A， Takeda A， et al. Enantioseparation of the carboxamide-type synthetic cannabinoids N-（1-amino-3-methyl-1-oxobutan-2-yl）-1-（5-fluoropentyl）-1H-indazole-3-carboxamide and methyl [1-（5-fluoropentyl）-1H-indazole-3-carbonyl]-valinate in illicit herbal products[J]. J Chromatogr A，2016，1473：83-89. doi：10.1016/j.chroma.2016.10.049 .
[30]	Longworth M， Banister S D， Mack J B C， et al. The 2-alkyl-2H-indazole regioisomers of synthetic cannabinoids AB-CHMINACA， AB-FUBINACA， AB-PINACA， and 5F-AB-PINACA are possible manufacturing impurities with cannabimimetic activities[J]. Forensic Toxicol，2016，34：286-303. doi：10. 1007/s11419-016-0316-y .
[31]	Ali S M， Kolieb E， Imbaby S， et al. Acute toxic effects of new synthetic cannabinoid on brain： Neurobehavioral and histological： Preclinical studies[J]. Chem Biol Interact，2023，370：110306. doi：10.1016/j.cbi.2022.110306 .
[32]	Gulekci Y， Efeoglu Ozseker P， Cavus Yonar F， et al. Comparison of methods to develop fingerprints on papers impregnated with AB-PINACA and AB-FUBINACA[J]. J Forensic Sci，2022，67（2）：524-533. doi：10.1111/1556-4029.14926 .
[33]	Lefever T W， Marusich J A， Thomas B F， et al. Vaping synthetic cannabinoids： A novel preclinical model of e-cigarette use in mice[J]. Subst Abuse，2017，11：1178221817701739. doi：10.1177/11782218 17701739 .
[34]	De Luca M A， Castelli M P， Loi B， et al. Native CB1 receptor affinity， intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids： BB-22， 5F-PB-22， 5F-AKB-48 and STS-135[J]. Neuropharmacology，2016，105：630-638. doi：10.1016/j.neuro pharm.2015.11.017 .
[35]	Dimmito M P， Stefanucci A， Pieretti S， et al. Discovery of orexant and anorexant agents with indazole scaffold endowed with peripheral antiedema activity[J]. Biomolecules，2019，9（9）：492. doi：10.3390/biom9090492 .
[36]	Krotulski A J， Garibay N， Walther D， et al. Pharmacokinetics and pharmacodynamics of the synthetic cannabinoid， 5F-MDMB-PICA， in male rats[J].Neuropharmacology，2021，199：108800. doi：10.1016/j.neuropharm.2021.108800 .
[37]	Wiley J L， Lefever T W， Glass M， et al. Do you feel it now? Route of administration and Δ⁹-tetrahydrocannabinol-like discriminative stimulus effects of synthetic cannabinoids in mice[J]. Neurotoxicology，2019，73：161-167. doi：10.1016/j.neuro. 2019.04.002 .
[38]	Gatch M B， Tourigny A， Shetty R A， et al. Behavioral pharmacology of five novel synthetic cannabinoids[J]. Behav Pharmacol，2022，33（2/3）：175-183. doi：10.1097/FBP.0000000000000618 .
[39]	Kaneko S. Motor vehicle collisions caused by the ‘super-strength’ synthetic cannabinoids， MAM-2201， 5F-PB-22， 5F-AB-PINACA， 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014[J]. Forensic Toxicol，2017，35（2）：244-251. doi：10.1007/s11419-017-0369-6 .
[40]	Kevin R C， Lefever T W， Snyder R W， et al. In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA[J]. Forensic Toxicol，2017，35（2）：333-347. doi：10.1007/s11419-017-0361-1 .
[41]	Hasegawa K， Wurita A， Minakata K， et al. Postmortem distribution of MAB-CHMINACA in body fluids and solid tissues of a human cadaver[J]. Forensic Toxicol，2015，33（2）：380-387. doi：10.1007/s11419-015-0272-y .
[42]	Gaunitz F， Lehmann S， Thomas A， et al. Post-mortem distribution of the synthetic cannabinoid MDMB-CHMICA and its metabolites in a case of combined drug intoxication[J]. Int J Legal Med，2018，132（6）：1645-1657. doi：10.1007/s00414-018-1911-8 .
[43]	Yamagishi I， Minakata K， Nozawa H， et al. A case of intoxication with a mixture of synthetic cannabinoids EAM-2201， AB-PINACA and AB-FUBINACA， and a synthetic cathinone α-PVP[J]. Leg Med （Tokyo），2018，35：44-49. doi：10.1016/j. legalmed.2018.08.004 .
[44]	Minakata K， Hasegawa K， Yamagishi I， et al. In vivo metabolites of AB-PINACA in solid tissues obtained from its abuser： Comparison with in vitro experiment[J]. J Anal Toxicol，2021，44（9）：1027-1035. doi：10.1093/jat/bkaa031 .
[45]	Ke X， Tian Y M， He D D， et al. Rapid simultaneous determination of three synthetic cannabinoids in urine and plasma of rats using ultra-high performance liquid chromatography tandem mass spectrome-try[J]. Toxics，2022，10（10）：619. doi：10.3390/toxics 10100619 .
[46]	Fabregat-Safont D， Mata-Pesquera M， Barneo-Muñoz M， et al. In-depth comparison of the metabolic and pharmacokinetic behaviour of the structurally related synthetic cannabinoids AMB-FUBINACA and AMB-CHMICA in rats[J]. Commun Biol，2022，5（1）：161. doi：10.1038/s42003-022-03113-5 .
[47]	Institóris L， Kovács K， Sija É， et al. Clinical symptoms and blood concentration of new psychoactive substances （NPS） in intoxicated and hospi‑ talized patients in the Budapest region of Hungary （2018-19）[J]. Clin Toxicol （Phila），2022，60（1）：18-24. doi：10.1080/15563650.2021.1928162 .
[48]	Wagmann L， Stiller R G， Fischmann S， et al. Going deeper into the toxicokinetics of synthetic canna-binoids： In vitro contribution of human carboxylesterases[J]. Arch Toxicol，2022，96（10）：2755-2766. doi：10.1007/s00204-022-03332-z .
[49]	Efeoglu Ozseker P， Daglioglu N， Gulmen M K， et al. Determination of AB-FUBINACA and 5F-NPB-22 in rats exposed to “Bonsai” via inhalation and analysis of seized product[J]. Leg Med （Tokyo），2021，50：101869. doi：10.1016/j.legalmed.2021.10 1869 .
[50]	Watanabe S， Vikingsson S， Åstrand A， et al. Biotransformation of the new synthetic cannabinoid with an alkene， MDMB-4en-PINACA， by human hepatocytes， human liver microsomes， and human urine and blood[J]. AAPS J，2019，22（1）：13. doi：10.1208/s12248-019-0381-3 .
[51]	Diao X X， Huestis M A. New synthetic cannabinoids metabolism and strategies to best identify optimal marker metabolites[J]. Front Chem，2019，7：109. doi：10.3389/fchem.2019.00109 .
[52]	Xiang J H， Wen D， Zhao J B， et al. Study of the metabolic profiles of “indazole-3-carboxamide” and “isatin acyl hydrazone” （OXIZID） synthetic cannabinoids in a human liver microsome model using UHPLC-QE Orbitrap MS[J]. Metabolites，2023，13（4）：576. doi：10.3390/metabo13040576 .
[53]	Yue L N， Xiang P， Shen B H， et al. Metabolism of 4F-MDMB-BICA in zebrafish by liquid chroma-tography-high resolution mass spectrometry[J]. Drug Test Anal，2021，13（6）：1223-1229. doi：10.1002/dta. 3019 .
[54]	Apirakkan O， Gavrilović I， Cowan D A， et al. In vitro phase I metabolic profiling of the synthetic cannabinoids AM-694， 5F-NNEI， FUB-APINACA， MFUBINAC， and AMB-FUBINACA[J]. Chem Res Toxicol，2020，33（7）：1653-1664. doi：10.1021/acs.chemrestox.9b00466 .
[55]	Erratico C， Negreira N， Norouzizadeh H， et al. In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA[J]. Drug Test Anal，2015，7（10）：866-876. doi：10.1002/dta.1796 .
[56]	Wang Z T， Fong C Y， Goh E M L， et al. Tran-sesterification of indazole-3-carboxamide synthetic cannabinoids： Identification of metabolite biomarkers for diagnosing co-abuse of 5F-MDMB-PINACA and alcohol[J]. J Anal Toxicol，2023，46（9）：1016-1024. doi：10.1093/jat/bkab121 .
[57]	Monti M C， Scheurer E， Mercer-Chalmers-Bender K. Phase I in vitro metabolic profiling of the synthetic cannabinoid receptor agonists CUMYL-THPINACA and ADAMANTYL-THPINACA[J]. Metabolites，2021，11（8）：470. doi：10.3390/metabo11080470 .
[58]	Presley B C， Logan B K， Jansen-Varnum S A. In vitro metabolic profile elucidation of synthetic cannabinoid APP-CHMINACA （PX-3）[J]. J Anal Toxicol，2020，44（3）：226-236. doi：10.1093/jat/bkz086 .
[59]	Giorgetti A， Brunetti P， Haschimi B， et al. Human phase-I metabolism and prevalence of two synthetic cannabinoids bearing an ethyl ester moiety： 5F-EDMB-PICA and EDMB-PINACA[J]. Drug Test Anal，2023，15（3）：299-313. doi：10.1002/dta.3405 .
[60]	Szpot P， Nowak K， Wachełko O， et al. Methyl （S）-2-（1-7（5-fluoropentyl）-1H-indole-3-carboxamido）- 3，3-dimethylbutanoate （5F-MDMB-PICA） intoxication in a child with identification of two new metabolites （ultra-high-performance liquid chromatogra-phy-tandem mass spectrometry）[J]. Forensic Toxicol，2023，41（1）：47-58. doi：10.1007/s11419-022-00629-7 .
[61]	Malaca S， Busardò F P， Gottardi M， et al. Dilute and shoot ultra-high performance liquid chromatography tandem mass spectrometry （UHPLC-MS/MS） analysis of psychoactive drugs in oral fluid[J]. J Pharm Biomed Anal，2019，170：63-67. doi：10.1016/j.jpba.2019.02.039 .
[62]	Franz F， Haschimi B， King L A， et al. Extraordinary long detection window of a synthetic cannabinoid metabolite in human urine — Potential impact on therapeutic decisions[J]. Drug Test Anal，2020， 12（3）：391-396. doi：10.1002/dta.2770 .
[63]	Lie W， Cheong E J Y， Goh E M L， et al. Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse[J]. Arch Toxicol，2021，95（2）：489-508. doi：10.1007/s00204-020-02948-3 .