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

A bioanalytical method for the detection of 25CN-NBOH has been developed.[23]

Literature

A review covering the literature up to 2020 was published in 2021.[24]

The tendency of the 4-cyano substitution to confer high 5-HT2A selectivity had previously been observed with DOCN,[25] 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),[26] 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.[27]

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.[28]

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. 598: 20–25. doi:10.1016/j.bbrc.2022.01.113. ISSN 0006-291X. PMID 35149433. S2CID 246548173.
  18. Ilchibaeva, Tatiana; Tsybko, Anton; Zeug, Andre; Müller, Franziska E.; Guseva, Daria; Bischoff, Stephan; Ponimaskin, Evgeni; Naumenko, Vladimir (January 2022). "Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes". Cells. 11 (15): 2384. doi:10.3390/cells11152384. ISSN 2073-4409. PMC 9368268. PMID 35954229.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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. 16 (21): 3263–3270. doi:10.1002/cmdc.202100395. ISSN 1860-7187. PMID 34288515. S2CID 236157499.
  25. 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.
  26. 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.
  27. "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.
  28. "The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014". www.legislation.gov.uk.
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