Synthesis, Analytical Characterization, and Human CB Receptor Binding Studies of the Chloroindole Analogues of the Synthetic Cannabinoid MDMB-CHMICA

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2024 Nov 27

PMID 39595590

Authors

Sascha Munster-Muller

Steven Hansen

Tobias Lucas

Arianna Giorgetti

Lukas Mogler

Svenja Fischmann

Folker Westphal

Volker Auwarter

Michael Putz

Till Opatz

Affiliations

Soon will be listed here.

Abstract

Synthetic cannabinoids (SCs) are one of the largest groups of new psychoactive substances (NPSs). However, the relationship between their chemical structure and the affinity to human CB receptors (hCB), which mediates their psychotropic activity, is not well understood. Herein, the synthesis of the 2-, 4-, 5-, 6- and 7-chloroindole analogues of the synthetic cannabimimetic MDMB-CHMICA, along with their analytical characterization via ultraviolet-visible (UV/VIS), infrared (IR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, is described. Furthermore, all five derivatives of MDMB-CHMICA were analyzed for their hCB binding affinities. Chlorination at position 4 and 5 of the indole core reduced the binding affinity compared to MDMB-CHMICA, while the test compounds chlorinated in positions 2, 6, and 7 largely retained their binding affinities relative to the non-chlorinated parent compound.

References

Pike E, Grafinger K, Cannaert A, Ametovski A, Luo J, Sparkes E . 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 CB receptor activation assays:.... Drug Test Anal. 2021; 13(7):1383-1401. DOI: 10.1002/dta.3037. View

Eissenstat M, Bell M, DAmbra T, Alexander E, DAUM S, ACKERMAN J . Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics. J Med Chem. 1995; 38(16):3094-105. DOI: 10.1021/jm00016a013. View

Pulver B, Fischmann S, Gallegos A, Christie R . EMCDDA framework and practical guidance for naming synthetic cannabinoids. Drug Test Anal. 2022; 15(3):255-276. DOI: 10.1002/dta.3403. View

Halter S, Angerer V, Rohrich J, Groth O, Roider G, Hermanns-Clausen M . Cumyl-PEGACLONE: A comparatively safe new synthetic cannabinoid receptor agonist entering the NPS market?. Drug Test Anal. 2018; 11(2):347-349. DOI: 10.1002/dta.2545. View

Banister S, Longworth M, Kevin R, Sachdev S, Santiago M, Stuart J . Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues. ACS Chem Neurosci. 2016; 7(9):1241-54. DOI: 10.1021/acschemneuro.6b00137. View

Hua T, Vemuri K, Nikas S, Laprairie R, Wu Y, Qu L . Crystal structures of agonist-bound human cannabinoid receptor CB. Nature. 2017; 547(7664):468-471. PMC: 5793864. DOI: 10.1038/nature23272. View

Abdel-Hay K, Belal T, Abiedalla Y, Thaxton-Weissenfluh A, Deruiter J, Smith F . Gas Chromatography-Mass Spectrometry (GC-MS) and Gas Chromatography-Infrared (GC-IR) Analyses of the Chloro-1- n-pentyl-3-(1-naphthoyl)-Indoles: Regioisomeric Cannabinoids. Appl Spectrosc. 2018; 73(4):433-443. DOI: 10.1177/0003702818809998. View

Frost J, Dart M, Tietje K, Garrison T, Grayson G, Daza A . Indol-3-yl-tetramethylcyclopropyl ketones: effects of indole ring substitution on CB2 cannabinoid receptor activity. J Med Chem. 2008; 51(6):1904-12. DOI: 10.1021/jm7011613. View

Castaneto M, Gorelick D, Desrosiers N, Hartman R, Pirard S, Huestis M . Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend. 2014; 144:12-41. PMC: 4253059. DOI: 10.1016/j.drugalcdep.2014.08.005. View

10.

Giorgetti A, Busardo F, Tittarelli R, Auwarter V, Giorgetti R . Post-Mortem Toxicology: A Systematic Review of Death Cases Involving Synthetic Cannabinoid Receptor Agonists. Front Psychiatry. 2020; 11:464. PMC: 7261860. DOI: 10.3389/fpsyt.2020.00464. View

11.

Haschimi B, Giorgetti A, Mogler L, Nagy T, Kramer S, Halter S . The Novel Psychoactive Substance Cumyl-CH-MEGACLONE: Human Phase-I Metabolism, Basic Pharmacological Characterization and Comparison to Other Synthetic Cannabinoid Receptor Agonists with a γ-Carboline-1-One Core. J Anal Toxicol. 2020; 45(3):277-290. DOI: 10.1093/jat/bkaa065. View

12.

Lin S, Khanolkar A, Fan P, Goutopoulos A, Qin C, Papahadjis D . Novel analogues of arachidonylethanolamide (anandamide): affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability. J Med Chem. 1999; 41(27):5353-61. DOI: 10.1021/jm970257g. View

13.

Kumar K, Shalev-Benami M, Robertson M, Hu H, Banister S, Hollingsworth S . Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell. 2019; 176(3):448-458.e12. PMC: 6461403. DOI: 10.1016/j.cell.2018.11.040. View

14.

Huffman J, Zengin G, Wu M, Lu J, Hynd G, Bushell K . Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem. 2004; 13(1):89-112. DOI: 10.1016/j.bmc.2004.09.050. View

15.

Adamowicz P . Fatal intoxication with synthetic cannabinoid MDMB-CHMICA. Forensic Sci Int. 2016; 261:e5-10. DOI: 10.1016/j.forsciint.2016.02.024. View

16.

Munster-Muller S, Hansen S, Opatz T, Zimmermann R, Putz M . Chemical profiling of the synthetic cannabinoid MDMB-CHMICA: Identification, assessment, and stability study of synthesis-related impurities in seized and synthesized samples. Drug Test Anal. 2019; 11(8):1192-1206. DOI: 10.1002/dta.2652. View

17.

Pertwee R . Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 2006; (168):1-51. DOI: 10.1007/3-540-26573-2_1. View

18.

Chaturvedi K, Anthony C, Pandey P, Doerksen R, Godfrey M . Influence of structural characteristics on the binding of synthetic cannabinoids from the JWH family to the CB1 receptor: A computational study. J Mol Graph Model. 2023; 126:108620. PMC: 10841904. DOI: 10.1016/j.jmgm.2023.108620. View

19.

Schoeder C, Hess C, Madea B, Meiler J, Muller C . Pharmacological evaluation of new constituents of "Spice": synthetic cannabinoids based on indole, indazole, benzimidazole and carbazole scaffolds. Forensic Toxicol. 2018; 36(2):385-403. PMC: 6002460. DOI: 10.1007/s11419-018-0415-z. View

20.

Norman C, Deventer M, Dremann O, Reid R, Van Uytfanghe K, Guillou C . In vitro cannabinoid receptor activity, metabolism, and detection in seized samples of CH-PIATA, a new indole-3-acetamide synthetic cannabinoid. Drug Test Anal. 2023; 16(4):380-391. DOI: 10.1002/dta.3555. View