25CN-NBOH

25CN-NBOH (sometimes also referred to as NBOH-2C-CN) is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT_2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT_2A receptor and with 100x selectivity for 5-HT_2A over 5-HT_2C, and 46x selectivity for 5-HT_2A over 5-HT_2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.

Structure

The structure of 25CN-NBOH in complex with an engineered Gαq heterotrimer of the 5-HT2AR has been determined by cryoelectron microscopy (cryo-EM), showing a distinct binding mode when compared to LSD.

Synthesis

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

Animal studies

25CN-NBOH was found to partially substitute for DOI but was considerably weaker at inducing a head-twitch response in mice. Another in vivo evaluation 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 Head Twitch Response (HTR) also refererred 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 5-HT2AR (measured via HTR) 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 5-HT2AR inverse agonist MDL100907.

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

Literature

A review covering the literature up to 2020 was published in 2021.

Related compounds

The tendency of the 4-cyano substitution to confer high 5-HT_2A selectivity had previously been observed with DOCN, but this 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 cyclised derivative 2S,6S-DMBMPP ((2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine), in binding assays, however it is also less complex to synthesise and has higher efficacy and selectivity in functional assays as a partial agonist of the 5-HT_2A receptor.

Legality

Hungary

25CN-NBOH is illegal in 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.

See also

• 25B-NBOH
• 25C-NBOH (NBOH-2CC)
• 25I-NBOH (NBOH-2CI)

References