25CN-NBOH
Psychedelic drug
From Wikipedia, the free encyclopedia
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]
- UK: Class A
- Illegal in Hungary
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| Other names | 2C-CN-NBOH; NBOH-2C-CN; N-(2-Hydroxybenzyl)-4-cyano-2,5-dimethoxyphenethylamine |
| Drug class | Selective serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen |
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| Formula | C18H20N2O3 |
| Molar mass | 312.369 g·mol−1 |
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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
| 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) 66–150% (Emax) |
| 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 | ND |
| SERT | >10,000 (Ki) |
| NET | >10,000 (Ki) |
| DAT | >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
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]
Physicochemical properties
The HCl-salt of 25CN-NBOH precipitates as a single and stable polymorph. The aqueous solubility of this salt is 8.5 mg/mL, leading to a solution with a pH of 6.24. A solution of 25CN-NBOH in water or buffer (pH 7.24) does not show any signs of degradation after 1 month at 25°C. The presence of an intramolecular hydrogen bond may help explain the high membrane permability.[36]
Detection
A bioanalytical method for the detection of 25CN-NBOH has been developed.[37]
Analogues
The tendency of the 4-cyano substitution to confer high selectivity for the serotonin 5-HT2A receptor had previously been observed with DOCN,[38] 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),[39] 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
Legal status
Canada
25CN-NBOH is a controlled substance in Canada under phenethylamine blanket-ban language.[40]
Hungary
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.[42]
United States
25CN-NBOH is not an explicitly controlled substance in the United States.[43] However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.