25CN-NBOH

Last updated

25CN-NBOH
NBOH-2CCN structure.png
Clinical data
Other names2C-CN-NBOH; NBOH-2C-CN; N-(2-Hydroxybenzyl)-4-cyano-2,5-dimethoxyphenethylamine
Drug class Selective serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
Legal status
Legal status
Identifiers
  • 4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H20N2O3
Molar mass 312.369 g·mol−1
3D model (JSmol)
  • COc1cc(C#N)c(OC)cc1CCNCc2ccccc2O
  • InChI=1S/C18H20N2O3/c1-22-17-10-15(11-19)18(23-2)9-13(17)7-8-20-12-14-5-3-4-6-16(14)21/h3-6,9-10,20-21H,7-8,12H2,1-2H3
  • Key:VWEDZTZAXHMZIL-UHFFFAOYSA-N

25CN-NBOH, also known as NBOH-2C-CN or as N-(2-hydroxybenzyl)-4-cyano-2,5-dimethoxyphenethylamine, is a psychedelic drug of the phenethylamine, 2C, and 25-NB (NBOH) families. [1] [2] It was developed and described in 2011 at the University of Copenhagen. [3] [4]

Contents

The drug is one of the most selective agonists of the serotonin 5-HT2A receptor known. [5] [6] [3] [7] [2] However, findings on its selectivity have varied, with some studies finding as little as 10-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor. [8] [2] [7] A much more selective derivative of 25CN-NBOH, TGF-8027, has since been described. [8]

A tritiated version of 25CN-NBOH has also been developed and used for more detailed investigations of the binding to serotonin 5-HT2 receptors and autoradiography. [9] In 2025, 25CN-NBOH was suggested as a possible alternative and replacement of DOI for use in scientific research. [10]

Interactions

Pharmacology

Pharmacodynamics

Actions

25CN-NBOH activities
Target Affinity (Ki, nM)
5-HT1A >10,000
5-HT1B >10,000
5-HT1D >10,000
5-HT1E >10,000
5-HT1F ND
5-HT2A 0.81–27 (Ki)
0.38–8.59 (EC50 Tooltip half-maximal effective concentration)
66–150% (Emax Tooltip maximal efficacy)
5-HT2B 30–75 (Ki)
59–145 (EC50)
57–60% (Emax)
5-HT2C 42–132 (Ki)
4.79–350 (EC50)
78–114% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A 6,591–>10,000
5-HT6 310–573
5-HT7 5,256–>10,000
α1A >10,000
α1B >10,000
α1D >10,000
α2A 803–>10,000
α2B 1,226–>10,000
α2C 543–2,900
β1 >10,000
β2 1,609
β3 >10,000
D1–D3 >10,000
D4 2,900–>10,000
D5 >10,000
H1 2,100–>10,000
H2 1,505
H3 >10,000 (guinea pig)
H4 >10,000
M1–M5 >10,000
I1 ND
σ1 (rat)280–284
σ2 (rat)120–575
MOR >10,000
DOR >10,000
KOR 4,200–>10,000
TAAR1 Tooltip Trace amine-associated receptor 1ND
SERT Tooltip Serotonin transporter>10,000 (Ki)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
DAT Tooltip Dopamine transporter>10,000 (Ki)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [2] [1] [3] [5] [7] [6] [11] [12] [13] [14]

25CN-NBOH is one of the most selective agonists of the serotonin 5-HT2A receptor yet discovered, with an affinity (Ki) of 1.32 nM at the human serotonin 5-HT2A receptor, 100-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor, and 46-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2B receptor. [5] [6] [3] [7] However, another study found that 25CN-NBOH only had around 25-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2B and 5-HT2C receptors. [2] [7] In any case, in 2020, 25CN-NBOH and the related drug (S,S)-DMBMPP were described as the most selective serotonin 5-HT2A receptor agonists discovered to date. [2] Subsequently, in 2025, it was reported that 25CN-NBOH had only 10-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor in the Gq dissociation assay, whereas its more recent derivative TGF-8027 showed 49-fold selectivity in the same assay. [8]

Effects

25CN-NBOH was found to partially substitute for DOI in drug discrimination tests but was considerably weaker at inducing the head-twitch response (HTR) in mice. [15] [16] As with DOI, 25CN-NBOH has shown a biphasic or inverted U-shaped dose–response curve in terms of HTR induction. [15] [17] In addition, as with many other psychedelics, tolerance and tachyphylaxis develop to the HTR induced by 25CN-NBOH. [17] A study of 25CN-NBOH concluded that "Given its distinct in vitro selectivity for 5-HT2A over non 5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity." [17]

25CN-NBOH induces the HTRs also referred to as "wet dog shakes" (WDS) in rodents and the cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior has been investigated in detail. [18]

Additional in-vivo investigations with this ligand has emerged. [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] Chronic administration in mice lead to desensitization of the serotonin 5-HT2A receptor (measured via HTR) and increased startle amplitude [29] whereas it does not effect reversal learning in mice. [30] 25CN-NBOH was shown to increase the production of CTGF in chondrocytes. [31] In rats, 25CN-NBOH induce a reduction in conditioned fear that was countered by pretreatment with the serotonin 5-HT2A receptor inverse agonist MDL100907. [32]

Notably, a single-dose of 25CN-NBOH enhances cognitive flexibility and reversal learning in mice weeks after administration [33] as well as functional plasticity and antidepressant like effects in rats through mechanisms independent of structural plasticity. [34]

Chemistry

Structure

Binding mode of 25CN-NBOH in the serotonin 5-HT2A receptor.

The structure of 25CN-NBOH in complex with an engineered Gαq heterotrimer of the serotonin 5-HT2A receptor has been determined by cryoelectron microscopy (cryo-EM), showing a distinct binding mode when compared to LSD. [11]

Synthesis

25CN-NBOH is readily available from 2C-H in 57% over 4 steps. [35]

Detection

A bioanalytical method for the detection of 25CN-NBOH has been developed. [36]

Analogues

The tendency of the 4-cyano substitution to confer high selectivity for the serotonin 5-HT2A receptor had previously been observed with DOCN, [37] but this drug was not sufficiently potent to be widely adopted as a research ligand. 25CN-NBOH is still slightly less selective for 5-HT2A than the more complex cyclized derivative 2S,6S-DMBMPP ((2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine), [38] in binding assays, however it is also less complex to synthesize and has higher efficacy and selectivity in functional assays as a partial agonist of the serotonin 5-HT2A receptor. Other analogues of 25CN-NBOH include 2C-CN and TGF-8027.

History

25CN-NBOH was first described in the scientific literature by Martin Hansen at the University of Copenhagen in 2011. [3] It was subsequently described more prominently, with its binding selectivity for the serotonin 5-HT2A receptor highlighted, by Hansen and colleagues in 2014 and 2015. [5] [15] A review covering the literature on 25CN-NBOH up to 2020 was published in 2021. [1] 25CN-NBOH was suggested as a possible alternative and replacement of DOI for use in scientific research in 2025. [10]

Society and culture

Hungary

25CN-NBOH is illegal in Hungary. [39]

United Kingdom

This substance is a Class A drug in the United Kingdom as a result of the N-benzylphenethylamine catch-all clause in the Misuse of Drugs Act 1971 . [40]

See also

References

  1. 1 2 3 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. S2CID   236157499.
  2. 1 2 3 4 5 6 Poulie CB, Jensen AA, Halberstadt AL, Kristensen JL (December 2020). "DARK Classics in Chemical Neuroscience: NBOMes". ACS Chem Neurosci. 11 (23): 3860–3869. doi:10.1021/acschemneuro.9b00528. PMC   9191638 . PMID   31657895.
  3. 1 2 3 4 5 Hansen M (2011). Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain (Ph.D. thesis). University of Copenhagen.
  4. ↑ "CNS Medicinal Chemistry in the Kristensen Group". Department of Drug Design and Pharmacology. University of Copenhagen. 25 March 2019.
  5. 1 2 3 4 Hansen M, Phonekeo K, Paine JS, Leth-Petersen S, Begtrup M, Bräuner-Osborne H, et al. (March 2014). "Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists". ACS Chemical Neuroscience. 5 (3): 243–249. doi:10.1021/cn400216u. PMC   3963123 . PMID   24397362.
  6. 1 2 3 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". J Pharmacol Exp Ther. 361 (3): 441–453. doi:10.1124/jpet.117.239905. PMID   28360333.
  7. 1 2 3 4 5 Halberstadt AL, Sindhunata IS, Scheffers K, Flynn AD, Sharp RF, Geyer MA, et al. (August 2016). "Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice". Neuropharmacology. 107: 364–375. doi:10.1016/j.neuropharm.2016.03.038. PMC   5403251 . PMID   27020041.
  8. 1 2 3 Fenske TG, McKee JL, Cavalco NG, Schalk SS, Bonniwell EM, Lammers JC, et al. (September 2025). "Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design". J Med Chem acs.jmedchem.5c01855. doi:10.1021/acs.jmedchem.5c01855. PMID   40997862.
  9. ↑ 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. S2CID   215802376.
  10. 1 2 Cameron LP, Jaster AM, Ramos R, Ullman EZ (2025). "The Utility of DOI For the Study of Serotonin 2A and 2C Receptors". Molecular Pharmacology 100093. doi:10.1016/j.molpha.2025.100093.
  11. 1 2 Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, et al. (September 2020). "Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor". Cell. 182 (6): 1574–1588.e19. doi:10.1016/j.cell.2020.08.024. PMC   7593816 . PMID   32946782.
  12. ↑ 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". J Med Chem. 65 (18): 12031–12043. doi:10.1021/acs.jmedchem.2c00702. PMC   9511481 . PMID   36099411.
  13. ↑ Marcher-Rørsted E, Nykodemová J, Harpsøe K, Jensen AA, Kristensen JL (March 2023). "Introducing Conformational Restraints on 25CN-NBOH: A Selective 5-HT2A Receptor Agonist". ACS Med Chem Lett. 14 (3): 319–325. doi:10.1021/acsmedchemlett.3c00014. PMC   10009789 . PMID   36923922.
  14. ↑ Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, et al. (December 2023). "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nat Commun. 14 (1) 8221. doi:10.1038/s41467-023-44016-1. PMC   10724237 . PMID   38102107.
  15. 1 2 3 Fantegrossi WE, Gray BW, Bailey JM, Smith DA, Hansen M, Kristensen JL (March 2015). "Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice". Psychopharmacology. 232 (6): 1039–1047. doi:10.1007/s00213-014-3739-3. PMC   4339409 . PMID   25224567.
  16. ↑ Halberstadt AL, van der Zee JV, Chatha M, Geyer MA, Powell SB (February 2019). "Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen". Psychopharmacology. 236 (2): 821–830. doi:10.1007/s00213-018-5118-y. PMC   6778591 . PMID   30448990.
  17. 1 2 3 Buchborn T, Lyons T, Knöpfel T (2018). "Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice". Frontiers in Pharmacology. 9 17. doi: 10.3389/fphar.2018.00017 . PMC   5808243 . PMID   29467649.
  18. ↑ Buchborn T, Lyons T, Song C, Feilding A, Knöpfel T (May 2023). "Cortical Correlates of Psychedelic-Induced Shaking Behavior Revealed by Voltage Imaging". International Journal of Molecular Sciences. 24 (11): 9463. doi: 10.3390/ijms24119463 . ISSN   1422-0067. PMC   10253917 . PMID   37298417.
  19. ↑ Harmon JL, Wills LP, McOmish CE, Demireva EY, Gingrich JA, Beeson CC, et al. (April 2016). "5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists". The Journal of Pharmacology and Experimental Therapeutics. 357 (1): 1–9. doi:10.1124/jpet.115.228395. PMC   4809314 . PMID   26787771.
  20. ↑ Odland AU, Jessen L, Kristensen JL, Fitzpatrick CM, Andreasen JT (February 2021). "The 5-hydroxytryptamine 2A receptor agonists DOI and 25CN-NBOH decrease marble burying and reverse 8-OH-DPAT-induced deficit in spontaneous alternation". Neuropharmacology. 183 107838. doi:10.1016/j.neuropharm.2019.107838. PMID   31693871. S2CID   207831116.
  21. ↑ Yang GE, Tae HJ, Lee TK, Park YE, Cho JH, Kim DW, et al. (September 2019). "Risperidone Treatment after Transient Ischemia Induces Hypothermia and Provides Neuroprotection in the Gerbil Hippocampus by Decreasing Oxidative Stress". International Journal of Molecular Sciences. 20 (18): 4621. doi: 10.3390/ijms20184621 . PMC   6770640 . PMID   31540405.
  22. ↑ Amodeo DA, Hassan O, Klein L, Halberstadt AL, Powell SB (October 2020). "Acute serotonin 2A receptor activation impairs behavioral flexibility in mice". Behavioural Brain Research. 395 112861. doi: 10.1016/j.bbr.2020.112861 . PMID   32814148.
  23. ↑ Xing L, Kalebic N, Namba T, Vaid S, Wimberger P, Huttner WB (December 2020). "Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex". Neuron. 108 (6): 1113–1129.e6. doi: 10.1016/j.neuron.2020.09.034 . PMID   33080227. S2CID   224775595.
  24. ↑ Elsilä LV, Korhonen N, Hyytiä P, Korpi ER (2020). "Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task". Frontiers in Pharmacology. 11 602770. doi: 10.3389/fphar.2020.602770 . PMC   7745734 . PMID   33343373.
  25. ↑ Liu X, Zhu H, Gao H, Tian X, Tan B, Su R (April 2022). "Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice". Biochemical and Biophysical Research Communications. 598: 20–25. doi:10.1016/j.bbrc.2022.01.113. PMID   35149433. S2CID   246548173.
  26. ↑ Ilchibaeva T, Tsybko A, Zeug A, Müller FE, Guseva D, Bischoff S, et al. (August 2022). "Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes". Cells. 11 (15): 2384. doi: 10.3390/cells11152384 . PMC   9368268 . PMID   35954229.
  27. ↑ Chen Y, Liu J, Yao Y, Yan H, Su R (2023-02-16). "Rearing behaviour in the mouse behavioural pattern monitor distinguishes the effects of psychedelics from those of lisuride and TBG". Frontiers in Pharmacology. 14 1021729. doi: 10.3389/fphar.2023.1021729 . PMC   9978355 . PMID   36874002.
  28. ↑ Schmitz GP, Chiu YT, Foglesong ML, Magee SN, MacKinnon M, König GM, et al. (2025). "Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation". Transl Psychiatry. 15 (1): 381. doi:10.1038/s41398-025-03611-0. PMC   12501219 . PMID   41052972.
  29. ↑ Tsybko AS, Ilchibaeva TV, Filimonova EA, Eremin DV, Popova NK, Naumenko VS (December 2020). "The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice". Neurochemical Research. 45 (12): 3059–3075. doi:10.1007/s11064-020-03153-5. PMID   33095437. S2CID   225052555.
  30. ↑ Odland AU, Kristensen JL, Andreasen JT (August 2021). "The selective 5-HT2A receptor agonist 25CN-NBOH does not affect reversal learning in mice". Behavioural Pharmacology. 32 (5): 448–452. doi:10.1097/FBP.0000000000000626. PMID   33595957. S2CID   231953516.
  31. ↑ Hori A, Nishida T, Takashiba S, Kubota S, Takigawa M (2017-11-16). "Regulatory mechanism of CCN2 production by serotonin (5-HT) via 5-HT2A and 5-HT2B receptors in chondrocytes". PLOS ONE. 12 (11) e0188014. Bibcode:2017PLoSO..1288014H. doi: 10.1371/journal.pone.0188014 . PMC   5690650 . PMID   29145495.
  32. ↑ Hagsäter SM, Pettersson R, Pettersson C, Atanasovski D, Näslund J, Eriksson E (September 2021). "A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear". The International Journal of Neuropsychopharmacology. 24 (9): 749–757. doi: 10.1093/ijnp/pyab040 . PMC   8453278 . PMID   34228806.
  33. ↑ Brouns EJ, Ekins TG, Ahmed OJ (2025-04-22). "Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration" . Psychedelics. 1: 1–7. doi:10.61373/pp025r.0002. ISSN   2997-268X. PMC   12341394 . PMID   40809535.
  34. ↑ Kramer HM, Hibicke M, Middleton J, Jaster AM, Kristensen JL, Nichols CD (November 2025). "Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity". Neuropsychopharmacology: 1–9. doi:10.1038/s41386-025-02272-3. PMID   41224969.
  35. ↑ Märcher-Rørsted E, Nykodemová J, Kristensen JL (2021-06-08). "An improved, scalable synthesis of the selective serotonin 2A receptor agonist 25CN-NBOH". SynOpen. 05 (2): a–1524–4439. doi: 10.1055/a-1524-4439 . ISSN   2509-9396.
  36. ↑ Breusova K, Ernstsen KG, Palner M, Linnet K, Kristensen JL, Kretschmann AC (May 2021). "A quantitative method for the selective 5-HT2A agonist 25CN-NBOH in rat plasma and brain". Journal of Pharmaceutical and Biomedical Analysis. 199 114016. doi:10.1016/j.jpba.2021.114016. PMID   33784574. S2CID   232431316.
  37. ↑ Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 359 (1): 1–6. doi:10.1007/PL00005315. PMID   9933142. S2CID   20150858.
  38. ↑ Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, et al. (January 2013). "Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands". ACS Chemical Neuroscience. 4 (1): 96–109. doi:10.1021/cn3000668. PMC   3547484 . PMID   23336049.
  39. ↑ "A Magyarországon megjelent, a Kábítószer és Kábítószer-függőség Európai Megfigyelő Központjának Korai Jelzőrendszerébe (EMCDDA EWS) 2005 óta bejelentett ellenőrzött anyagok büntetőjogi vonatkozású besorolása" [The criminal law-related classification of controlled substances announced in 2005 in the Early Warning System of the European Monitoring Center for Drugs and Drug Addiction (EMCDDA EWS) in Hungary](PDF) (in Hungarian). September 2015.
  40. ↑ "The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014". UK Statutory Instruments 2014 No. 1106. www.legislation.gov.uk.
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