25CN-NBOH

Source: Wikipedia, the free encyclopedia.
25CN-NBOH
Clinical data
Other namesNBOH-2C-CN
Legal status
Legal status
Identifiers
  • 4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile
JSmol)
  • COc1cc(C#N)c(OC)cc1CCNCc2ccccc2O
  • InChI=1S/C18H20N2O3/c1-22-17-10-15(11-19)18(23-2)9-13(17)7-8-20-12-14-5-3-4-6-16(14)21/h3-6,9-10,20-21H,7-8,12H2,1-2H3
  • Key:VWEDZTZAXHMZIL-UHFFFAOYSA-N

25CN-NBOH (sometimes also referred to as NBOH-2C-CN)[1] is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen.[2] This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B.[3][4][5][6] 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.[7]

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.[8]

Bindingmode of 25CN-NBOH in 5-HT2AR

Synthesis

25CN-NBOH is readily available from 2C-H in 57% over 4 steps.[9]

Animal studies

25CN-NBOH was found to partially substitute for DOI but was considerably weaker at inducing a head-twitch response in mice.[10][11] Another in vivo evaluation 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."[12]

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.[13]

Additional in vivo investigations with this ligand has emerged.[14][15][16][17][18][19][20][21] Chronic administration in mice lead to desensitization of the 5-HT2AR (measured via HTR) and increased startle amplitude[22] whereas it does not effect reversal learning in mice.[23] 25CN-NBOH was shown to increase the production of CTGF in chondrocytes.[24] In rats, 25CN-NBOH induce a reduction in conditioned fear that was countered by pretreatment with 5-HT2AR inverse agonist MDL100907.[25]

A bioanalytical method for the detection of 25CN-NBOH has been developed.[26]

Literature

A review covering the literature up to 2020 was published in 2021.[27]

Related compounds

The tendency of the 4-cyano substitution to confer high 5-HT2A selectivity had previously been observed with DOCN,

2S,6S-DMBMPP ((2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine),[29] 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-HT2A receptor.

(2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine

Legality

Hungary

25CN-NBOH is illegal in Hungary.[30]

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.[31]

See also

References

  1. ^ "25CN-NBOH". Chemical Probes.
  2. ^ "CNS Medicinal Chemistry in the Kristensen Group". Department of Drug Design and Pharmacology. University of Copenhagen. 25 March 2019.
  3. PMID 24397362
    .
  4. PMID 28360333
    .
  5. ^ Hansen M (2011). Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain (Ph.D. thesis). University of Copenhagen.
  6. PMID 27020041
    .
  7. S2CID 215802376
    .
  8. PMID 32946782
    .
  9. ISSN 2509-9396
    .
  10. PMID 25224567
    .
  11. PMID 30448990
    .
  12. PMID 29467649
    .
  13. PMID 37298417
    .
  14. PMID 26787771
    .
  15. S2CID 207831116
    .
  16. PMID 31540405
    .
  17. PMID 32814148
    .
  18. S2CID 224775595
    .
  19. PMID 33343373
    .
  20. S2CID 246548173
    .
  21. PMID 35954229
    .
  22. S2CID 225052555
    .
  23. S2CID 231953516
    .
  24. PMID 29145495
    .
  25. PMID 34228806
    .
  26. S2CID 232431316
    .
  27. S2CID 236157499
    .
  28. S2CID 20150858
    .
  29. PMID 23336049
    .
  30. ^ "A Magyarországon megjelent, a Kábítószer és Kábítószer-függőség Európai Megfigyelő Központjának Korai Jelzőrendszerébe (EMCDDA EWS) 2005 óta bejelentett ellenőrzött anyagok büntetőjogi vonatkozású besorolása" [The criminal law-related classification of controlled substances announced in 2005 in the Early Warning System of the European Monitoring Center for Drugs and Drug Addiction (EMCDDA EWS) in Hungary] (PDF) (in Hungarian). September 2015.
  31. ^ "The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014". UK Statutory Instruments 2014 No. 1106. www.legislation.gov.uk.
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