2C-CN
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| Other names | 25CN; 2,5-Dimethoxy-4-cyanophenethylamine; 4-Cyano-2,5-dimethoxyphenethylamine |
| Routes of administration | Oral[1] |
| Drug class | Serotonin receptor modulator; Serotonin 5-HT2 receptor agonist; Serotonin 5-HT2A receptor agonist; Possible serotonergic psychedelic or hallucinogen |
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| Chemical and physical data | |
| Formula | C11H14N2O2 |
| Molar mass | 206.245 g·mol−1 |
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2C-CN, also known as 4-cyano-2,5-dimethoxyphenethylamine, is a serotonin receptor modulator and possible serotonergic psychedelic of the phenethylamine and 2C families.[2][3][4][5][6][7][8]
Use and effects
[edit]2C-CN was previously not known to have been tested in humans and it was unknown whether it produces psychedelic effects.[2][3] According to Daniel Trachsel however, 2C-CN was inactive at a dose of 10 mg orally, whereas a dose of 22 mg orally possibly produced threshold effects.[1]
Interactions
[edit]Pharmacology
[edit]Pharmacodynamics
[edit]2C-CN is a serotonin 5-HT2 receptor partial to full agonist, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.[4][9] Its EC50 (Emax) values were 78–503 nM (73–91%) at the serotonin 5-HT2A receptor, 650 nM (82%) at the serotonin 5-HT2B receptor, and 140 nM (101%) at the serotonin 5-HT2C receptor.[4][9] The drug was 10-fold or more less potent as a serotonin 5-HT2A receptor agonist than other notable 2C psychedelics including 2C-B, 2C-D, 2C-T, 2C-P, and 2C-T-7.[9][4]
Chemistry
[edit]Synthesis
[edit]The chemical synthesis of 2C-CN has been described.[9][5]
Derivatives
[edit]2C-CN is the 2C parent compound of potent serotonin 5-HT2A receptor agonists of the 25-NB family including 25CN-NBOH, 25CN-NBOMe, 25CN-NBF, and 25CN-NBMD, among others.[10][11][12][8][13][14] 25CN-NBOH is notable in being one of the most selective serotonin 5-HT2A receptor agonists known.[10][13] In addition, 25-NB derivatives of 2C-CN are known that act as β-arrestin-biased serotonin 5-HT2A receptor agonists.[8]
History
[edit]2C-CN was first described in the scientific literature by 1984.[5] It was briefly mentioned by Alexander Shulgin in his books PiHKAL (Phenethylamines I Have Known and Loved) (1991) and The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds (2011).[2][3] Daniel Trachsel described 2C-CN's preliminary properties and effects in humans in 2013.[1] The drug's pharmacology was elucidated in the mid-2020s.[9][4]
See also
[edit]References
[edit]- ^ a b c Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. ISBN 978-3-03788-700-4. OCLC 858805226. Retrieved 31 January 2025.
Die Substanz 2C-CN (186) [87] trägt eine Nitrilgruppe in der 4-Position. Aufgrund der polaren Nitrilgruppe und den tieferen Affinitäten des 3C-Analogons DOCN (187) zum 5-HT2A-Rezeptor (siehe Tabelle 10) kann eine schwache Aktivität im Menschen vermutet werden. Das deckt sich mit ersten Versuchen am Menschen, wonach 10mg 2C-CN (186) oral keinerlei Effekte zeigten und 22mg lediglich als mögliche Schwellendosis bezeichnet wurden.
- ^ a b c Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628. "The treatment of the 2C-B phthalimide described above, with cuprous cyanide rather than cuprous chloride, gave rise to the cyano analog which, on hydrolysis with hydrazine, yielded 2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with hot, strong base gave the corresponding acid, 2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of either of these compounds has been made in the human animal, as far as I know."
- ^ a b c Shulgin A, Manning T, Daley PF (2011). "#55. DOCN". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley, CA: Transform Press. pp. 105–106. ISBN 978-0-9630096-3-0. OCLC 709667010.
- ^ a b c d e Fenske TG, McKee JL, Cavalco NG, Schalk SS, Bonniwell EM, Lammers JC, et al. (October 2025). "Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design". J Med Chem. 68 (19): 20619–20635. doi:10.1021/acs.jmedchem.5c01855. PMID 40997862.
To probe the EPB tolerance for α-substitution, we initially synthesized compound TGF-8027 (1) from 2C−CN and 2′-hydroxyacetophenone via reductive amination (Scheme 1).21 [...] By contrast, compound activities containing a 4-CN, including 2C−CN, 25CN-NBOH, and TGF-8027 (1), were substantially reduced at the m5-HT2A receptor but largely spared at the m5-HT2C receptor isoform (Figure 7B−D), overall leading to reduced m5-HT2A over m5-HT2C selectivity (Table 4). [...] Table 4. Parameter Estimates for m5-HT2A and m5-HT2C Measuring Gq Dissociation by BRETa [...] 2C−CN was purchased from Enamine (Monmouth, NJ). [...] 2C−CN, 4-cyano-2,5-dimethoxyphenethylamine [...] Table S1. Parameter estimates for 5-HT2A, 5-HT2B, and 5-HT2C measuring Gq dissociation by BRET. [...]
- ^ a b c Cheng AC, Castagnoli N (April 1984). "Synthesis and physicochemical and neurotoxicity studies of 1-(4-substituted-2,5-dihydroxyphenyl)-2-aminoethane analogues of 6-hydroxydopamine". Journal of Medicinal Chemistry. 27 (4): 513–520. doi:10.1021/jm00370a014. PMID 6423824.
- ^ Leth-Petersen S, Bundgaard C, Hansen M, Carnerup MA, Kehler J, Kristensen JL (October 2014). "Correlating the metabolic stability of psychedelic 5-HT₂A agonists with anecdotal reports of human oral bioavailability". Neurochemical Research. 39 (10): 2018–2023. doi:10.1007/s11064-014-1253-y. PMID 24519542.
- ^ Märcher-Rørsted E, Nykodemová J, Kristensen JL (April 2021). "An improved, scalable synthesis of the selective serotonin 2A receptor agonist 25CN-NBOH". Synopen. 5 (2): 158–160. doi:10.1055/a-1524-4439.
- ^ a b c Poulie CB, Pottie E, Simon IA, Harpsøe K, D'Andrea L, Komarov IV, et al. (September 2022). "Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists". Journal of Medicinal Chemistry. 65 (18): 12031–12043. doi:10.1021/acs.jmedchem.2c00702. PMC 9511481. PMID 36099411.
- ^ a b c d e Pottie E, Poulie CB, Simon IA, Harpsøe K, D'Andrea L, Komarov IV, et al. (August 2023). "Structure-Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists". ACS Chem Neurosci. 14 (15): 2727–2742. doi:10.1021/acschemneuro.3c00267. PMC 10401645. PMID 37474114.
- ^ a b Märcher Rørsted E, Jensen AA, Kristensen JL (November 2021). "25CN-NBOH: A Selective Agonist for in vitro and in vivo Investigations of the Serotonin 2A Receptor". ChemMedChem. 16 (21): 3263–3270. doi:10.1002/cmdc.202100395. PMID 34288515.
- ^ Jensen AA, McCorvy JD, Leth-Petersen S, Bundgaard C, Liebscher G, Kenakin TP, et al. (June 2017). "Detailed Characterization of the In Vitro Pharmacological and Pharmacokinetic Properties of N-(2-Hydroxybenzyl)-2,5-Dimethoxy-4-Cyanophenylethylamine (25CN-NBOH), a Highly Selective and Brain-Penetrant 5-HT2A Receptor Agonist". The Journal of Pharmacology and Experimental Therapeutics. 361 (3): 441–453. doi:10.1124/jpet.117.239905. PMID 28360333.
- ^ Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, et al. (July 2020). "The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH". Biochemical Pharmacology. 177 113979. doi:10.1016/j.bcp.2020.113979. PMID 32298690.
- ^ a b Poulie CB, Jensen AA, Halberstadt AL, Kristensen JL (December 2020). "DARK Classics in Chemical Neuroscience: NBOMes". ACS Chemical Neuroscience. 11 (23): 3860–3869. doi:10.1021/acschemneuro.9b00528. PMC 9191638. PMID 31657895.
- ^ Slocum ST, DiBerto JF, Roth BL (July 2022). "Molecular insights into psychedelic drug action". Journal of Neurochemistry. 162 (1): 24–38. doi:10.1111/jnc.15540. PMID 34797943.