25CN-NBOH

25CN-NBOH
Clinical data
Other namesNBOH-2C-CN
Legal status
Legal status
Identifiers
IUPAC name
  • 4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC18H20N2O3
Molar mass312.369 g·mol−1
3D model (JSmol)
SMILES
  • COc1cc(C#N)c(OC)cc1CCNCc2ccccc2O
InChI
  • 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

Pharmacology

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 by a group of researchers at the University of Copenhagen. 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.[1][2][3][4] 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.[5]

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.[6]

Bindingmode of 25CN-NBOH in 5-HT2AR

Synthesis

25CN-NBOH is readily available from 2C-H in 57% over 4 steps.[7]

Animal studies

25CN-NBOH was found to partially substitute for DOI but was considerably weaker at inducing a head-twitch response in mice.[8][9] 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."[10] Additional in vivo investigations with this ligand is emerging.[11][12][13][14][15][16][17] Chronic administration in mice lead to desensitization of the 5-HT2AR (measured via HTR) and increased startle amplitude[18] whereas it does not effect reversal learning in mice.[19] 25CN-NBOH was shown to increase the production of CTGF in chondrocytes.[20] In rats, 25CN-NBOH induce a reduction in conditioned fear that was countered by pretreatment with 5-HT2AR inverse agonist MDL100907.[21]

A bioanalytical method for the detection of 25CN-NBOH has been developed.[22]

Literature

A review covering the literature up to 2020 was published in 2021.[23]

The tendency of the 4-cyano substitution to confer high 5-HT2A selectivity had previously been observed with DOCN,[24] 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 cyclised derivative 2S,6S-DMBMPP ((2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine),[25] 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.[26]

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.[27]

See also

References

  1. ↑ Hansen M, Phonekeo K, Paine JS, Leth-Petersen S, Begtrup M, Bräuner-Osborne H, Kristensen JL (March 2014). "Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists". ACS Chemical Neuroscience. 5 (3): 243–9. doi:10.1021/cn400216u. PMC 3963123. PMID 24397362.
  2. ↑ Jensen AA, McCorvy JD, Leth-Petersen S, Bundgaard C, Liebscher G, Kenakin TP, et al. (June 2017). "2A Receptor Agonist". The Journal of Pharmacology and Experimental Therapeutics. 361 (3): 441–453. doi:10.1124/jpet.117.239905. PMID 28360333.
  3. ↑ 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.
  4. ↑ Halberstadt AL, Sindhunata IS, Scheffers K, Flynn AD, Sharp RF, Geyer MA, Young JW (August 2016). "Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice". Neuropharmacology. 107: 364–375. doi:10.1016/j.neuropharm.2016.03.038. PMC 5403251. PMID 27020041.
  5. ↑ Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, et al. (July 2020). "3H]25CN-NBOH". Biochemical Pharmacology. 177: 113979. doi:10.1016/j.bcp.2020.113979. PMID 32298690. S2CID 215802376.
  6. ↑ Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, et al. (September 2020). "2A Serotonin Receptor". Cell. 182 (6): 1574–1588.e19. doi:10.1016/j.cell.2020.08.024. PMC 7593816. PMID 32946782.
  7. ↑ Marcher-Rørsted, Emil; Nykodemova, Jitka; Kristensen, Jesper Langgaard (2021-06-08). "An improved, scalable synthesis of the selective serotonin 2A receptor agonist 25CN-NBOH". SynOpen. 05 (2): a–1524–4439. doi:10.1055/a-1524-4439. ISSN 2509-9396.
  8. ↑ Fantegrossi WE, Gray BW, Bailey JM, Smith DA, Hansen M, Kristensen JL (March 2015). "Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice". Psychopharmacology. 232 (6): 1039–47. doi:10.1007/s00213-014-3739-3. PMC 4339409. PMID 25224567.
  9. ↑ Halberstadt AL, van der Zee JV, Chatha M, Geyer MA, Powell SB (February 2019). "Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen". Psychopharmacology. 236 (2): 821–830. doi:10.1007/s00213-018-5118-y. PMC 6778591. PMID 30448990.
  10. ↑ Buchborn T, Lyons T, Knöpfel T (2018). "Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice". Frontiers in Pharmacology. 9: 17. doi:10.3389/fphar.2018.00017. PMC 5808243. PMID 29467649.
  11. ↑ Harmon, J. L.; Wills, L. P.; McOmish, C. E.; Demireva, E. Y.; Gingrich, J. A.; Beeson, C. C.; Schnellmann, R. G. (2016-03-01). "5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists". Journal of Pharmacology and Experimental Therapeutics. 357 (1): 1–9. doi:10.1124/jpet.115.228395. ISSN 1521-0103. PMC 4809314. PMID 26787771.
  12. ↑ Odland AU, Jessen L, Kristensen JL, Fitzpatrick CM, Andreasen JT (November 2019). "The 5-hydroxytryptamine 2A receptor agonists DOI and 25CN-NBOH decrease marble burying and reverse 8-OH-DPAT-induced deficit in spontaneous alternation". Neuropharmacology. 183: 107838. doi:10.1016/j.neuropharm.2019.107838. PMID 31693871. S2CID 207831116.
  13. ↑ Yang, Go Eun; Tae, Hyun-Jin; Lee, Tae-Kyeong; Park, Young Eun; Cho, Jeong Hwi; Kim, Dae Won; Park, Joon Ha; Ahn, Ji Hyeon; Ryoo, Sungwoo; Kim, Young-Myeong; Shin, Myoung Cheol (2019-09-18). "Risperidone Treatment after Transient Ischemia Induces Hypothermia and Provides Neuroprotection in the Gerbil Hippocampus by Decreasing Oxidative Stress". International Journal of Molecular Sciences. 20 (18): 4621. doi:10.3390/ijms20184621. ISSN 1422-0067. PMC 6770640. PMID 31540405.
  14. ↑ Amodeo DA, Hassan O, Klein L, Halberstadt AL, Powell SB (October 2020). "Acute serotonin 2A receptor activation impairs behavioral flexibility in mice". Behavioural Brain Research. 395: 112861. doi:10.1016/j.bbr.2020.112861. PMID 32814148.
  15. ↑ Xing, Lei; Kalebic, Nereo; Namba, Takashi; Vaid, Samir; Wimberger, Pauline; Huttner, Wieland B. (October 2020). "Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex". Neuron. 108 (6): 1113–1129.e6. doi:10.1016/j.neuron.2020.09.034. PMID 33080227. S2CID 224775595.
  16. ↑ Elsilä, Lauri V.; Korhonen, Nuppu; Hyytiä, Petri; Korpi, Esa R. (2020). "Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task". Frontiers in Pharmacology. 11: 602770. doi:10.3389/fphar.2020.602770. ISSN 1663-9812. PMC 7745734. PMID 33343373.
  17. ↑ Liu, Xiaoqian; Zhu, Huili; Gao, Huan; Tian, Xiangyun; Tan, Bo; Su, Ruibin (2022-02-01). "Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice". Biochemical and Biophysical Research Communications. doi:10.1016/j.bbrc.2022.01.113. ISSN 0006-291X. S2CID 246548173.
  18. ↑ Tsybko AS, Ilchibaeva TV, Filimonova EA, Eremin DV, Popova NK, Naumenko VS (October 2020). "2A Receptor Agonists Affects the Behavior and the BDNF System in Mice". Neurochemical Research. 45 (12): 3059–3075. doi:10.1007/s11064-020-03153-5. PMID 33095437. S2CID 225052555.
  19. ↑ Odland, Anna U.; Kristensen, Jesper L.; Andreasen, Jesper T. (2021-02-15). "The selective 5-HT2A receptor agonist 25CN-NBOH does not affect reversal learning in mice". Behavioural Pharmacology. 32 (5): 448–452. doi:10.1097/FBP.0000000000000626. ISSN 1473-5849. PMID 33595957. S2CID 231953516.
  20. ↑ Hori A, Nishida T, Takashiba S, Kubota S, Takigawa M (2017-11-16). "Regulatory mechanism of CCN2 production by serotonin (5-HT) via 5-HT2A and 5-HT2B receptors in chondrocytes". PLOS ONE. 12 (11): e0188014. Bibcode:2017PLoSO..1288014H. doi:10.1371/journal.pone.0188014. PMC 5690650. PMID 29145495.
  21. ↑ Hagsäter, Sven Melker; Pettersson, Robert; Pettersson, Christopher; Atanasovski, Daniela; Näslund, Jakob; Eriksson, Elias (2021-07-06). "A complex impact of systemically administered 5-HT2A receptor ligands on conditioned fear". International Journal of Neuropsychopharmacology. 24 (pyab040): 749–757. doi:10.1093/ijnp/pyab040. ISSN 1461-1457. PMC 8453278. PMID 34228806.
  22. ↑ Breusova, Kateryna; Ernstsen, Kristian Goldeman; Palner, Mikael; Linnet, Kristian; Kristensen, Jesper Langgaard; Kretschmann, Andreas Christopher (2021-03-08). "A quantitative method for the selective 5-HT2A agonist 25CN-NBOH in rat plasma and brain". Journal of Pharmaceutical and Biomedical Analysis. 199: 114016. doi:10.1016/j.jpba.2021.114016. ISSN 0731-7085. PMID 33784574. S2CID 232431316.
  23. ↑ Märcher-Rørsted, Emil; Jensen, Anders A.; Kristensen, Jesper Langgaard (2021). "25CN-NBOH: A selective agonist for in vitro and in vivo investigations of the serotonin 2A receptor". ChemMedChem. n/a (n/a): 3263–3270. doi:10.1002/cmdc.202100395. ISSN 1860-7187. PMID 34288515. S2CID 236157499.
  24. ↑ Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 359 (1): 1–6. doi:10.1007/PL00005315. PMID 9933142. S2CID 20150858.
  25. ↑ Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, et al. (January 2013). "Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands". ACS Chemical Neuroscience. 4 (1): 96–109. doi:10.1021/cn3000668. PMC 3547484. PMID 23336049.
  26. ↑ "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.
  27. ↑ "The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014". www.legislation.gov.uk.


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