25CN-NBOH

25CN-NBOH, also known as NBOH-2C-CN or as N--4-cyano-2,5-dimethoxyphenethylamine, is a psychedelic drug of the phenethylamine, 2C, and 25-NB families. It was developed and described in 2011 at the University of Copenhagen.
The drug is one of the most selective agonists of the serotonin 5-HT_2A receptor known. However, findings on its selectivity have varied, with some studies finding as little as 10-fold selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor. A much more selective derivative of 25CN-NBOH, TGF-8027, has since been described.
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. In 2025, 25CN-NBOH was suggested as a possible alternative and replacement of DOI for use in scientific research.

Pharmacology

Pharmacodynamics

Actions

25CN-NBOH is one of the most selective agonists of the serotonin 5-HT_2A receptor yet discovered, with an affinity of 1.32nM at the human serotonin 5-HT_2A receptor, 100-fold selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor, and 46-fold selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2B receptor. However, another study found that 25CN-NBOH only had around 25-fold selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2B and 5-HT_2C receptors. In any case, in 2020, 25CN-NBOH and the related drug (S,''S'')-DMBMPP were described as the most selective serotonin 5-HT_2A receptor agonists discovered to date. Subsequently, in 2025, it was reported that 25CN-NBOH had only 10-fold selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor in the G_q dissociation assay, whereas its more recent derivative TGF-8027 showed 49-fold selectivity in the same assay.

Effects

25CN-NBOH was found to partially substitute for DOI in drug discrimination tests but was considerably weaker at inducing the head-twitch response in mice. As with DOI, 25CN-NBOH has shown a biphasic or inverted U-shaped dose–response curve in terms of HTR induction. In addition, as with many other psychedelics, tolerance and tachyphylaxis develop to the HTR induced by 25CN-NBOH. A study of 25CN-NBOH concluded that "Given its distinct in vitro selectivity for 5-HT_2A 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-HT_2A related psychoactivity."
25CN-NBOH induces the HTRs also referred to as "wet dog shakes" in rodents and the cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior has been investigated in detail.
Additional in-vivo investigations with this ligand has emerged. Chronic administration in mice lead to desensitization of the serotonin 5-HT_2A receptor and increased startle amplitude whereas it does not effect reversal learning in mice. 25CN-NBOH was shown to increase the production of CTGF in chondrocytes. In rats, 25CN-NBOH induce a reduction in conditioned fear that was countered by pretreatment with the serotonin 5-HT_2A receptor inverse agonist MDL100907.
Notably, a single-dose of 25CN-NBOH enhances cognitive flexibility and reversal learning in mice weeks after administration as well as functional plasticity and antidepressant like effects in rats through mechanisms independent of structural plasticity.

Chemistry

Structure

The structure of 25CN-NBOH in complex with an engineered Gα_q heterotrimer of the serotonin 5-HT_2A receptor has been determined by cryoelectron microscopy, showing a distinct binding mode when compared to LSD.

Synthesis

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

Physicochemical properties

The HCl-salt of 25CN-NBOH precipitates as a single and stable polymorph. The aqueous solubillity 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 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 permabillity.

Detection

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

Analogues

The tendency of the 4-cyano substitution to confer high selectivity for the serotonin 5-HT_2A receptor had previously been observed with DOCN, but this drug was not sufficiently potent to be widely adopted as a research ligand. 25CN-NBOH is still slightly less selective for 5-HT_2A than the more complex cyclized derivative 2S,6S-DMBMPP -2--6-, 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-HT_2A 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. It was subsequently described more prominently, with its binding selectivity for the serotonin 5-HT_2A receptor highlighted, by Hansen and colleagues in 2014 and 2015. A review covering the literature on 25CN-NBOH up to 2020 was published in 2021. 25CN-NBOH was suggested as a possible alternative and replacement of DOI for use in scientific research in 2025.

Society and culture

Legal status

Canada

25CN-NBOH is a controlled substance in Canada under phenethylamine blanket-ban language.

Hungary

25CN-NBOH is illegal in Hungary.

United States

25CN-NBOH is not an explicitly controlled substance in the United States. However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.