Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues
<p>Chemical structures of serotonin and the classic serotonergic psychedelics, psilocybin, and its active metabolite psilocin, <span class="html-italic">N</span>,<span class="html-italic">N</span>-dimethyltryptamine (DMT), mescaline and lysergic acid diethylamide (LSD).</p> "> Figure 2
<p>Phenethylamine-based psychedelics. Chemical structures of 2,5-dimethoxyphenethylamines (2C) drugs and their corresponding <span class="html-italic">N</span>-(2-methoxybenzyl)phenethylamines (NBOMe) drugs. Phenethylamine scaffold is outlined.</p> "> Figure 3
<p>Concentration–response (cell death) curves of the tested drugs (0–1500 µM) obtained, in differentiated SH-SY5Y cells, by the neutral red uptake and the resazurin reduction assays, 24 h after exposure. Results are presented as mean ± 95% CI of at least 4 independent experiments (performed in triplicate). The concentration–response curves were drawn using the least squares method as a fitting method. CI—confidence interval.</p> "> Figure 4
<p>Impact of the cytochrome P450 (CYP)-mediated metabolism on the cytotoxicity of the tested drugs assessed through the neutral red uptake assay, in differentiated SH-SY5Y cells, 24 h after exposure to the drugs in the presence or absence of different CYP inhibitors: 1000 μM ABT (non-selective CYP inhibitor), 10 μM quinidine (CYP2D6 inhibitor) or 1μM ketoconazole (CYP3A4 inhibitor). Results are presented as mean ± SD of at least 4 independent experiments (performed in triplicate). Statistical comparisons were performed using two-way ANOVA, followed by Tukey’s multiple comparison post hoc test [* <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001 vs. control (0 μM)]. In all cases, <span class="html-italic">p</span> values < 0.05 were considered statistically significant.</p> "> Figure 5
<p>Effect of monoamine oxidase (MAO) inhibition on the drugs-induced cytotoxicity in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs, in the presence or absence of two MAO inhibitors: 1 μM clorgyline—MAO-A inhibitor or 1 μM rasagiline—MAO-B inhibitor, through the neutral red uptake assay. The results are presented as mean ± SD of at least 4 independent experiments (performed in triplicate). Statistical comparisons were performed using two-way ANOVA, followed by Tukey’s multiple comparison post hoc test [* <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001 vs. control (0 μM)]. In all cases, <span class="html-italic">p</span> values < 0.05 were considered statistically significant.</p> "> Figure 6
<p>Mitochondrial membrane potential, evaluated with the JC-1 dye, in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs. The results were calculated as red/green fluorescence intensity ratios and expressed as percentage of control cells. Results are presented as mean ± SD of at least 3 independent experiments (performed in triplicate). As positive control, carbonyl cyanide m-chlorophenyl hydrazone (100 µM, 4 h) was used. Statistical comparisons were performed using one-way ANOVA, followed by Dunnett’s multiple comparison post hoc test. [*** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001 vs. control (0 μM)]. In all cases, <span class="html-italic">p</span> values < 0.05 were considered statistically significant.</p> "> Figure 7
<p>Intracellular levels of total glutathione, evaluated through the DTNB-GSH recycling assay, in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs. Results are presented as mean ± SD of at least 5 independent experiments (performed in duplicate). Statistical comparisons were performed using one-way ANOVA, followed by Dunnett’s multiple comparison post hoc test. [*** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001 vs. control (0 μM)]. In all cases, <span class="html-italic">p</span> values < 0.05 were considered statistically significant.</p> "> Figure 8
<p>Intracellular adenosine triphosphate (ATP) levels, evaluated through an ATP bioluminescence assay, in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs. Results are presented as mean ± SD of at least 4 independent experiments (performed in duplicate). Statistical comparisons were performed using one-way ANOVA, followed by Dunnett’s multiple comparison post hoc test. [* <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001 vs. control (0 μM)]. In all cases, <span class="html-italic">p</span> values < 0.05 were considered statistically significant.</p> "> Figure 9
<p>Concentration–response (cell death) curves of the tested drugs (0–2000 µM) obtained in HepG2 cells by the neutral red uptake and the resazurin reduction assays, 24 h after exposure. Results are presented as mean ± 95% CI of at least 4 independent experiments (performed in triplicate). The concentration–response curves were drawn using the least squares method as a fitting method. CI—confidence interval.</p> "> Figure 10
<p>Impact of the metabolism via cytochrome P450 (CYP) on the cytotoxicity of the tested drugs assessed through the resazurin reduction uptake assay, in HepG2 cells, 24 h after exposure to the drugs in the presence or absence of different CYP inhibitors: 1000 μM ABT (non-selective CYP inhibitor), 10 μM quinidine (CYP2D6 inhibitor) or 1μM ketoconazole (CYP3A4 inhibitor). Results are presented as mean ± SD of at least 4 independent experiments (performed in triplicate). Statistical comparisons were performed using two-way ANOVA, followed by Tukey’s multiple comparison post hoc test [* <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001 vs. control (0 μM)]. In all cases, <span class="html-italic">p</span> values < 0.05 were considered statistically significant.</p> "> Figure 11
<p>Correlations between EC<sub>50</sub> values obtained in both metabolic and lysosomal activity measurements (cytotoxicity assays) in both cell lines tested with the lipophilicity (<b>A</b>) and calculated passive permeability (<b>B</b>).</p> ">
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Evaluation of Drug Lipophilicity and Interaction with Phospholipidic Membranes
2.3. Evaluation of Drugs BBB Permeability
2.4. Neurotoxic Profile of 2C Phenethylamines and Their NBOMe Counterparts
2.5. Effect on Neuronal Oxidative Stress
2.6. Effect of Cytochrome P450 Inhibition on Drug-Induced Neurotoxicity
2.7. Effect of Monoamine Oxidase Inhibition on Drug-Induced Neurotoxicity
2.8. Effect of the Drugs on the Neuronal Mitochondrial Membrane Potential
2.9. Effect of the Drugs on Intracellular Glutathione Levels
2.10. Effect of the Drugs on Intracellular Adenosine Triphosphate Levels
2.11. Hepatotoxic Profile of 2C Phenethylamines and Their NBOMe Counterparts
2.12. Effect of the Drugs on Hepatic Oxidative Stress
2.13. Effect of Cytochrome P450 Inhibition on Drug-Induced Hepatotoxicity
2.14. Structure–Property–Cytotoxicity Relationships
3. Materials and Methods
3.1. Chemistry
3.1.1. Reagents and General Conditions
3.1.2. Synthesis of 2C and NBOMe Drugs
Synthesis of β-Nitrostyrene Derivatives
- Synthesis of 2,5-Dimethoxy-β-nitrostyrene
- Synthesis of 3,4,5-dimethoxy-β-nitrostyrene
- Synthesis of 2,5-Dimethoxyphenethylamine (2C-H) and Mescaline
- Synthesis of 4-Bromo-2,5-dimethoxy-β-phenethylamine (2C-B)
- Synthesis of 2,5-Dimethoxy-4-nitro-dimethoxy-β-phenethylamine (2C-N)
- Synthesis of N-(2-methoxybenzyl)phenethylamines (NBOMes)
3.2. Evaluation of Drug-like Properties
3.2.1. Reagents and General Conditions
3.2.2. Evaluation of the CHI
3.2.3. Evaluation of the CHI on IAM
3.2.4. Evaluation of BBB Permeability
3.3. Evaluation of Human Monoamine Oxidase (hMAO) Inhibitory Activity
3.3.1. Materials
3.3.2. Human Monoamine Oxidase (hMAO) Inhibitory Activity Assay
3.4. In Vitro Toxicological Studies
3.4.1. Reagents and General Conditions
3.4.2. SH-SY5Y Cell Culture and Differentiation
3.4.3. HepG2 Cell Culture
3.4.4. Evaluation of Drugs Cytotoxicity
3.4.5. Assessment of Intracellular Redox State
3.4.6. Determination of Cytochrome P450 Inhibition Activity
3.4.7. Determination of MAO Inhibition Activity
3.4.8. Determination of Mitochondrial Membrane Potential
3.4.9. Determination of Intracellular Total Glutathione
3.4.10. Determination of Intracellular Adenosine Triphosphate
3.5. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
2C-B | 4-Bromo-2,5-dimethoxy-β-phenethylamine |
2C-H | 2,5-Dimethoxyphenethylamine |
ABT | 1-Aminobenzotriazole |
ATP | Adenosine 5′-triphosphate |
BSA | Bovine Serum Albumin |
CCCP | 2-[2-(3-Chlorophenyl)hydrazinylyidene]propanedinitrile |
CYP450 | Cytochrome P450 |
DCFH-DA | 2′,7′-Dichlorofluorescin Diacetate |
DMEM | Dulbecco’s Modified Eagle’s Medium |
DMSO | Dimethyl sulfoxide |
DTNB | 5,5′-Dithiobis (2-nitrobenzoic acid) |
EDTA | Disodium salt dihydrate |
EI-MS | Electron Impact Mass Spectrometry |
EMCDDA | European Monitoring Centre for Drugs and Drug Addiction |
EWA | Early Warning Advisory |
FBS | Fetal Bovine Serum |
GSH | Glutathione |
HBSS | Hanks’ Balanced Salt Solution |
NADPH | β-Nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt |
NMR | Nuclear Magnetic Resonance |
RNS | Reactive Nitrogen Species |
ROS | Reactive Oxygen Species |
TNB | 5-Thio-2-nitrobenzoic acid |
TPA | Phorbol 12-myristate 13-acetate |
UNODC | United Nations Office on Drugs and Crime |
UV | Ultra-Violet |
References
- Nichols, D.E. Psychedelics. Pharmacol. Rev. 2016, 68, 264–355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nichols, D.E. Hallucinogens. Pharmacol. Ther. 2004, 101, 131–181. [Google Scholar] [CrossRef]
- Hendricks, P.S.; Thorne, C.B.; Clark, C.B.; Coombs, D.W.; Johnson, M.W. Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. J. Psychopharmacol. 2015, 29, 280–288. [Google Scholar] [CrossRef]
- Johansen, P.O.; Krebs, T.S. Psychedelics not linked to mental health problems or suicidal behavior: A population study. J. Psychopharmacol. 2015, 29, 270–279. [Google Scholar] [CrossRef] [PubMed]
- Klock, J.C.; Boerner, U.; Becker, C.E. Coma, hyperthermia, and bleeding associated with massive LSD overdose, a report of eight cases. Clin. Toxicol. 1975, 8, 191–203. [Google Scholar] [CrossRef]
- Nichols, D.E.; Grob, C.S. Is LSD toxic? Forensic Sci. Int. 2018, 284, 141–145. [Google Scholar] [CrossRef]
- Le Dare, B.; Gicquel, T.; Baert, A.; Morel, I.; Bouvet, R. Self-inflicted neck wounds under influence of lysergic acid diethylamide: A case report and literature review. Medicine 2020, 99, e20868. [Google Scholar] [CrossRef] [PubMed]
- Reynolds, P.C.; Jindrich, E.J. A mescaline associated fatality. J. Anal. Toxicol. 1985, 9, 183–184. [Google Scholar] [CrossRef] [PubMed]
- Nichols, D.E.; Fantegrossi, W.E. Emerging designer drugs. In The Effects of Drug Abuse on the Human Nervous System; Madras, B., Kuhar, M., Eds.; Elsevier: Amsterdam, The Netherlands, 2014; pp. 575–596. ISBN 9780124186798. [Google Scholar]
- United Nations Office on Drugs and Crime. The Challenge of New Psychoactive Substances; Global SMART Programme; UNODC: Vienna, Austria, 2013. [Google Scholar]
- European Monitoring Centre for Drugs and Drug Addiction. European Drug Report 2020: Trends and Developments; Publications Office of the European Union: Luxembourg, 2020. [Google Scholar]
- European Monitoring Centre for Drugs and Drug Addiction. Annual Report 2009: The State of the Drugs Problem in Europe; Publications Office of the European Union: Luxembourg, 2009. [Google Scholar]
- Shulgin, A.; Shulgin, A. PiHKAL: A Chemical Love Story; Transform Press: Berkeley, CA, USA, 1991; ISBN 9780963009616. [Google Scholar]
- Heim, R. Synthese und Pharmakologie Potenter 5-HT2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur Entwicklung Eines Neuen Struktur-Wirkungskonzepts. Ph.D. Thesis, Freie Universität Berlin, Berlin, Germany, 2003. [Google Scholar]
- Halberstadt, A.L. Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens. Curr. Top. Behav. Neurosci. 2017, 32, 283–311. [Google Scholar] [CrossRef]
- Rickli, A.; Luethi, D.; Reinisch, J.; Buchy, D.; Hoener, M.C.; Liechti, M.E. Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology 2015, 99, 546–553. [Google Scholar] [CrossRef] [Green Version]
- Andreasen, M.F.; Telving, R.; Rosendal, I.; Eg, M.B.; Hasselstrom, J.B.; Andersen, L.V. A fatal poisoning involving 25C-NBOMe. Forensic Sci. Int. 2015, 251, e1–e8. [Google Scholar] [CrossRef]
- Hill, S.L.; Doris, T.; Gurung, S.; Katebe, S.; Lomas, A.; Dunn, M.; Blain, P.; Thomas, S.H. Severe clinical toxicity associated with analytically confirmed recreational use of 25I-NBOMe: Case series. Clin. Toxicol. 2013, 51, 487–492. [Google Scholar] [CrossRef]
- Lowe, L.M.; Peterson, B.L.; Couper, F.J. A Case Review of the First Analytically Confirmed 25I-NBOMe-Related Death in Washington State. J. Anal. Toxicol. 2015, 39, 668–671. [Google Scholar] [CrossRef] [Green Version]
- Waldman, W.; Kala, M.; Lechowicz, W.; Gil, D.; Anand, J.S. Severe clinical toxicity caused by 25I-NBOMe confirmed analytically using LC-MS-MS method. Acta Biochim. Pol. 2018, 65, 567–571. [Google Scholar] [CrossRef]
- Milhazes, N.; Cunha-Oliveira, T.; Martins, P.; Garrido, J.; Oliveira, C.; Rego, A.C.; Borges, F. Synthesis and cytotoxic profile of 3,4-methylenedioxymethamphetamine (“ecstasy”) and its metabolites on undifferentiated PC12 cells: A putative structure-toxicity relationship. Chem. Res. Toxicol. 2006, 19, 1294–1304. [Google Scholar] [CrossRef]
- Hansen, M. Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain. Ph.D. Thesis, Det Farmaceutiske Fakultet, København, Denmark, 2010. [Google Scholar]
- Valkó, K.; Bevan, C.; Reynolds, D. Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC: A High-Throughput Alternative to log P/log D. Anal. Chem. 1997, 69, 2022–2029. [Google Scholar] [CrossRef] [PubMed]
- Valko, K.; Du, C.M.; Bevan, C.D.; Reynolds, D.P.; Abraham, M.H. Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: Comparison with other lipophilicity measures. J. Pharm. Sci. 2000, 89, 1085–1096. [Google Scholar] [CrossRef]
- Valko, K. Physicochemical and Biomimetic Properties in Drug Discovery: Chromatographic Techniques for Lead Optimization; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2014; ISBN 978-1-118-81744-5. [Google Scholar]
- Fernandes, C.; Pinto, M.; Martins, C.; Gomes, M.J.; Sarmento, B.; Oliveira, P.J.; Remião, F.; Borges, F. Development of a PEGylated-Based Platform for Efficient Delivery of Dietary Antioxidants Across the Blood–Brain Barrier. Bioconj. Chem. 2018, 29, 1677–1689. [Google Scholar] [CrossRef]
- Kim, H.; Xue, X. Detection of Total Reactive Oxygen Species in Adherent Cells by 2′,7′-Dichlorodihydrofluorescein Diacetate Staining. J. Vis. Exp. 2020, 160, e60682. [Google Scholar] [CrossRef]
- Bach, A.W.; Lan, N.C.; Johnson, D.L.; Abell, C.W.; Bembenek, M.E.; Kwan, S.W.; Seeburg, P.H.; Shih, J.C. cDNA cloning of human liver monoamine oxidase A and B: Molecular basis of differences in enzymatic properties. Proc. Natl. Acad. Sci. USA 1988, 85, 4934–4938. [Google Scholar] [CrossRef] [PubMed]
- Cossarizza, A.; Baccarani-Contri, M.; Kalashnikova, G.; Franceschi, C. A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem. Biophys. Res. Commun. 1993, 197, 40–45. [Google Scholar] [CrossRef]
- Reers, M.; Smiley, S.T.; Mottola-Hartshorn, C.; Chen, A.; Lin, M.; Chen, L.B. Mitochondrial membrane potential monitored by JC-1 dye. Methods Enzymol. 1995, 260, 406–417. [Google Scholar] [CrossRef]
- Rahman, I.; Kode, A.; Biswas, S.K. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat. Protoc. 2006, 1, 3159–3165. [Google Scholar] [CrossRef] [PubMed]
- Arbo, M.D.; Silva, R.; Barbosa, D.J.; Dias da Silva, D.; Silva, S.P.; Teixeira, J.P.; Bastos, M.L.; Carmo, H. In vitro neurotoxicity evaluation of piperazine designer drugs in differentiated human neuroblastoma SH-SY5Y cells. J. Appl. Toxicol. 2016, 36, 121–130. [Google Scholar] [CrossRef] [PubMed]
- Reis, J.; Fernandes, C.; Salem, H.; Maia, M.; Tomé, C.; Benfeito, S.; Teixeira, J.; Oliveira, P.J.; Uriarte, E.; Ortuso, F.; et al. Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties. Eur. J. Med. Chem. 2022, 239, 114507. [Google Scholar] [CrossRef] [PubMed]
- Repetto, G.; del Peso, A.; Zurita, J.L. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat. Protoc. 2008, 3, 1125–1131. [Google Scholar] [CrossRef]
- Niles, A.L.; Moravec, R.A.; Riss, T.L. Update on in vitro cytotoxicity assays for drug development. Expert Opin. Drug Discov. 2008, 3, 655–669. [Google Scholar] [CrossRef]
Drugs | CHI LogD7.4 | Kpcell | HBD a | NRB a | TPSA a (Å2) | BBB Prediction a |
---|---|---|---|---|---|---|
2C-B | 0.70 | 3.08 | 1 | 4 | 46.1 | No |
2C-N | 0.37 | 0.94 | 1 | 5 | 91.9 | No |
Mescaline-NBOMe | 1.34 | 2.71 | 1 | 8 | 53.5 | Yes |
25B-NBOMe | 2.32 | 9.08 | 1 | 8 | 44.3 | Yes |
25N-NBOMe | 1.96 | 5.05 | 1 | 9 | 90.1 | Yes |
Compounds | −Log Pe ± SD | Prediction |
---|---|---|
Verapamil | 4.4 ± 0.34 | |
Lidocaine | 4.8 ± 0.39 | |
Quinidine. HCl | 4.8 ± 0.39 | |
Progesterone | 4.5 ± 0.44 | |
Propanolol. HCl | 4.6 ± 0.42 | |
Theophilline | 6.8 ± 0.39 | |
Corticosterone | 5.0 ± 0.37 | |
Mescaline-NBOMe.HCl | 4.7 ± 0.49 | |
25B-NBOMe.HCl | 4.4 ± 0.36 | |
25N-NBOMe.HCl | 4.6 ± 0.34 |
Neutral Red Uptake | ||||||
---|---|---|---|---|---|---|
Mesc | 2C-B | 2C-N | Mesc-NBOMe | 25B-NBOMe | 25N-NBOMe | |
EC50 | NA | 164.6 | 732.7 | 405.6 (****) | 33.86 (****) | 125.0 (****) |
Top | NA | 93.68 | ≈100 | 98.57 | 87.85 | 87.38 |
Bottom | NA | 1.900 | 6.911 | 1.218 | 0.08250 | 2.841 |
Hill Slope | NA | 1.746 | 2.691 | 2.681 | 2.687 | 5.758 |
Curve p value (comparison between the 2C-X and 25X-NBOMe curves) | - | - | - | <0.0001 | <0.0001 | <0.0001 |
Resazurin Reduction | ||||||
EC50 | NA | 224.9 | 832.0 | 677.2 (****) | 58.36 (****) | 154.1 (****) |
Top | NA | 83.95 | ≈100 | 94.72 | 80.62 | 80.10 |
Bottom | NA | 7.210 | 4.440 | 2.774 | 6.827 | 0.9223 |
Hill Slope | NA | 1.670 | 1.627 | 2.524 | 4.464 | 4.692 |
Curve p value (comparison between the 2C-X and 25X-NBOMe curves) | - | - | - | <0.0001 | <0.0001 | <0.0001 |
Neutral Red Uptake | ||||||
---|---|---|---|---|---|---|
Mesc | 2C-B | 2C-N | Mesc-NBOMe | 25B-NBOMe | 25N-NBOMe | |
EC50 | NA | 257.2 | 960.0 | 476.2 (****) | 34.70 (****) | 114.7 (****) |
Top | NA | 95.01 | ≈100 | 98.25 | ≈100 | 94.13 |
Bottom | NA | 5.433 | 7.328 | 2.853 | 4.279 | 7.254 |
Hill Slope | NA | 5.413 | 4.340 | 3.666 | 2.442 | 6.518 |
Curve p value (comparison between the 2C-X and 25X-NBOMe curves) | - | - | - | <0.0001 | <0.0001 | <0.0001 |
Resazurin Reduction | ||||||
EC50 | NA | 206.0 | 833.9 | 425.9 (****) | 32.82 (****) | 99.68 (****) |
Top | NA | 89.29 | ≈100 | 87.43 | 89.49 | 87.26 |
Bottom | NA | 1.072 | 0.2545 | −0.3754 | 4.552 | 3.464 |
Hill Slope | NA | 3.731 | 2.334 | 3.411 | 3.079 | 5.089 |
Curve p value (comparison between the 2C-X and 25X-NBOMe curves) | - | - | - | <0.0001 | <0.0001 | <0.0001 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Martins, D.; Gil-Martins, E.; Cagide, F.; da Fonseca, C.; Benfeito, S.; Fernandes, C.; Chavarria, D.; Remião, F.; Silva, R.; Borges, F. Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues. Pharmaceuticals 2023, 16, 1158. https://doi.org/10.3390/ph16081158
Martins D, Gil-Martins E, Cagide F, da Fonseca C, Benfeito S, Fernandes C, Chavarria D, Remião F, Silva R, Borges F. Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues. Pharmaceuticals. 2023; 16(8):1158. https://doi.org/10.3390/ph16081158
Chicago/Turabian StyleMartins, Daniel, Eva Gil-Martins, Fernando Cagide, Catarina da Fonseca, Sofia Benfeito, Carlos Fernandes, Daniel Chavarria, Fernando Remião, Renata Silva, and Fernanda Borges. 2023. "Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues" Pharmaceuticals 16, no. 8: 1158. https://doi.org/10.3390/ph16081158