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| Clinical data | |
|---|---|
| Other names | NBOH-2C-CN |
| Drug class | Selectiveserotonin5-HT2A receptoragonist |
| Legal status | |
| Legal status | |
| Identifiers | |
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| CAS Number | |
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| Chemical and physical data | |
| Formula | C18H20N2O3 |
| Molar mass | 312.369 g·mol−1 |
| 3D model (JSmol) | |
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25CN-NBOH, also known asNBOH-2C-CN,[1] is a compound indirectly derived from thephenethylamine series ofhallucinogens, which was discovered in 2014 at theUniversity of Copenhagen.[2] It is a member of theNBOMe family ofpsychedelics.[3]
The drug is notable in being one of the mostselectiveagonists of theserotonin5-HT2A receptor known.[4][5][6][7][3]
A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to serotonin5-HT2 receptors andautoradiography.[8]
| 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 (EC50Tooltip half-maximal effective concentration) 66–150% (EmaxTooltip 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 |
| TAAR1Tooltip Trace amine-associated receptor 1 | ND |
| SERTTooltip Serotonin transporter | >10,000 (Ki) |
| NETTooltip Norepinephrine transporter | >10,000 (Ki) |
| DATTooltip 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:[3][9][10][4][7][5][11][12][13][14] | |
25CN-NBOH is notable as one of the mostselectiveagonists of theserotonin5-HT2A receptor yet discovered, with anaffinity (pKi) of 8.88 at the human serotonin 5-HT2A receptor, 100-fold selectivity for the serotonin 5-HT2A receptor over the serotonin5-HT2C receptor, and 46-fold selectivity for the serotonin 5-HT2A receptor over the serotonin5-HT2B receptor.[4][5][6][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.[3][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.[3]
25CN-NBOH was found to partially substitute forDOI indrug discrimination tests but was considerably weaker at inducing thehead-twitch response (HTR) in mice.[15][16] As with DOI, 25CN-NBOH has shown a biphasic orinverted U-shapeddose–response curve in terms of HTR induction.[15][17] In addition, as with many other psychedelics,tolerance andtachyphylaxis 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 5-HT2AR (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 ofCTGF inchondrocytes.[31] In rats, 25CN-NBOH induce a reduction in conditioned fear that was countered by pretreatment with 5-HT2AR 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]
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.[11]
25CN-NBOH is readily available from 2C-H in 57% over 4 steps.[35]
A bioanalytical method for the detection of 25CN-NBOH has been developed.[36]
The tendency of the 4-cyano substitution to confer high 5-HT2A selectivity had previously been observed with DOCN,[37] but this 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 derivative2S,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 apartial agonist of the 5-HT2A receptor.
A review covering the literature up to 2020 was published in 2021.[9]
25CN-NBOH is illegal in Hungary.[39]
This substance is aClass A drug in the United Kingdom as a result of theN-benzylphenethylamine catch-all clause in theMisuse of Drugs Act 1971.[40]
