Pharmacology

'
25CN-NBOH
'' (sometimes also referred to as NBOH-2C-CN) is a compound indirectly derived from the phenethylamine series of

hallucinogen Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...

s, which was discovered in 2014 b
a group of researchers
at the

University of Copenhagen The University of Copenhagen ( da, Københavns Universitet, KU) is a prestigious public research university in Copenhagen, Denmark. Founded in 1479, the University of Copenhagen is the second-oldest university in Scandinavia after Uppsala Unive ...

. This compound is notable as one of the most selective agonist ligands for the 5-HT_2A

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

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 The head-twitch response (HTR) is a rapid side-to-side head movement that occurs in mice and rats after the serotonin 5-HT2A receptor is activated. The prefrontal cortex may be the neuroanatomical locus mediating the HTR. Many serotonergic hallucino ...

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."'' Additional in vivo investigations with this ligand is emerging. 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 CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). CTGF has important roles in many ...

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 2''S'',6''S''-DMBMPP ((2''S'',6''S'')-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 In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

of the 5-HT_2A receptor.

Legality

Hungary

25CN-NBOH is illegal in Hungary.

United Kingdom

References

{{Phenethylamines 25-NB (psychedelics) 5-HT2A agonists