25CN-NBOH explained

Iupac Name:4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile
Width:240px
Legal Uk:Class A
Legal Status:Illegal in Hungary
Cas Number:1391489-32-9
Unii:32CN2DQE3Q
Pubchem:90489020
Chemspiderid:58191431
Synonyms:NBOH-2C-CN
C:18
H:20
N:2
O:3
Smiles:COc1cc(C#N)c(OC)cc1CCNCc2ccccc2O
Stdinchi: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
Stdinchikey: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]

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,[28] 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),[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.

Legality

Hungary

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

United Kingdom

See also

Notes and References

  1. Web site: 25CN-NBOH . Chemical Probes .
  2. Web site: CNS Medicinal Chemistry in the Kristensen Group . Department of Drug Design and Pharmacology. 25 March 2019 . University of Copenhagen .
  3. Hansen M, Phonekeo K, Paine JS, Leth-Petersen S, Begtrup M, Bräuner-Osborne H, Kristensen JL . Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists . ACS Chemical Neuroscience . 5 . 3 . 243–249 . March 2014 . 24397362 . 3963123 . 10.1021/cn400216u .
  4. Jensen AA, McCorvy JD, Leth-Petersen S, Bundgaard C, Liebscher G, Kenakin TP, Bräuner-Osborne H, Kehler J, Kristensen JL . 6 . Detailed Characterization of the In Vitro Pharmacological and Pharmacokinetic Properties of N-(2-Hydroxybenzyl)-2,5-Dimethoxy-4-Cyanophenylethylamine (25CN-NBOH), a Highly Selective and Brain-Penetrant 5-HT2A Receptor Agonist . The Journal of Pharmacology and Experimental Therapeutics . 361 . 3 . 441–453 . June 2017 . 28360333 . 10.1124/jpet.117.239905 . free .
  5. Ph.D. . Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain. . Hansen M . vanc . University of Copenhagen . 2011 .
  6. Halberstadt AL, Sindhunata IS, Scheffers K, Flynn AD, Sharp RF, Geyer MA, Young JW . Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice . Neuropharmacology . 107 . 364–375 . August 2016 . 27020041 . 5403251 . 10.1016/j.neuropharm.2016.03.038 .
  7. Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, Liebscher G, Hansen M, Bräuner-Osborne H, Palner M, Andreasen JT, Kristensen JL . 6 . The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [<sup>3</sup>H]25CN-NBOH . Biochemical Pharmacology . 177 . 113979 . July 2020 . 32298690 . 10.1016/j.bcp.2020.113979 . 215802376 .
  8. Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, Wacker D, Robertson MJ, Seven AB, Nichols DE, Shoichet BK, Skiniotis G, Roth BL . 6 . Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor . English . Cell . 182 . 6 . 1574–1588.e19 . September 2020 . 32946782 . 7593816 . 10.1016/j.cell.2020.08.024 .
  9. Märcher-Rørsted E, Nykodemová J, Kristensen JL . 2021-06-08. An improved, scalable synthesis of the selective serotonin 2A receptor agonist 25CN-NBOH. SynOpen. 05. 2. en. a–1524–4439. 10.1055/a-1524-4439. 2509-9396. free.
  10. Fantegrossi WE, Gray BW, Bailey JM, Smith DA, Hansen M, Kristensen JL . 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 . 1039–1047 . March 2015 . 25224567 . 4339409 . 10.1007/s00213-014-3739-3 .
  11. Halberstadt AL, van der Zee JV, Chatha M, Geyer MA, Powell SB . Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen . Psychopharmacology . 236 . 2 . 821–830 . February 2019 . 30448990 . 6778591 . 10.1007/s00213-018-5118-y .
  12. Buchborn T, Lyons T, Knöpfel T . Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice . Frontiers in Pharmacology . 9 . 17 . 2018 . 29467649 . 5808243 . 10.3389/fphar.2018.00017 . free .
  13. Buchborn T, Lyons T, Song C, Feilding A, Knöpfel T . May 2023 . Cortical Correlates of Psychedelic-Induced Shaking Behavior Revealed by Voltage Imaging . International Journal of Molecular Sciences . en . 24 . 11 . 9463 . 10.3390/ijms24119463 . 37298417 . 10253917 . 1422-0067 . free .
  14. Harmon JL, Wills LP, McOmish CE, Demireva EY, Gingrich JA, Beeson CC, Schnellmann RG . 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists . The Journal of Pharmacology and Experimental Therapeutics . 357 . 1 . 1–9 . April 2016 . 26787771 . 4809314 . 10.1124/jpet.115.228395 .
  15. Odland AU, Jessen L, Kristensen JL, Fitzpatrick CM, Andreasen JT . 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 . February 2021 . 31693871 . 10.1016/j.neuropharm.2019.107838 . 207831116 .
  16. Yang GE, Tae HJ, Lee TK, Park YE, Cho JH, Kim DW, Park JH, Ahn JH, Ryoo S, Kim YM, Shin MC, Cho JH, Lee CH, Hwang IK, Jin H, Won MH, Lee JC . 6 . 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 . September 2019 . 31540405 . 6770640 . 10.3390/ijms20184621 . free .
  17. Amodeo DA, Hassan O, Klein L, Halberstadt AL, Powell SB . Acute serotonin 2A receptor activation impairs behavioral flexibility in mice . Behavioural Brain Research . 395 . 112861 . October 2020 . 32814148 . 10.1016/j.bbr.2020.112861 . free .
  18. Xing L, Kalebic N, Namba T, Vaid S, Wimberger P, Huttner WB . Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex . Neuron . 108 . 6 . 1113–1129.e6 . December 2020 . 33080227 . 10.1016/j.neuron.2020.09.034 . 224775595 . free .
  19. Elsilä LV, Korhonen N, Hyytiä P, Korpi ER . Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task . English . Frontiers in Pharmacology . 11 . 602770 . 2020 . 33343373 . 7745734 . 10.3389/fphar.2020.602770 . free .
  20. Liu X, Zhu H, Gao H, Tian X, Tan B, Su R . Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice . Biochemical and Biophysical Research Communications . 598 . 20–25 . April 2022 . 35149433 . 10.1016/j.bbrc.2022.01.113 . 246548173 .
  21. Ilchibaeva T, Tsybko A, Zeug A, Müller FE, Guseva D, Bischoff S, Ponimaskin E, Naumenko V . 6 . Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes . Cells . 11 . 15 . 2384 . August 2022 . 35954229 . 9368268 . 10.3390/cells11152384 . free .
  22. Tsybko AS, Ilchibaeva TV, Filimonova EA, Eremin DV, Popova NK, Naumenko VS . The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice . Neurochemical Research . 45 . 12 . 3059–3075 . December 2020 . 33095437 . 10.1007/s11064-020-03153-5 . 225052555 .
  23. Odland AU, Kristensen JL, Andreasen JT . The selective 5-HT2A receptor agonist 25CN-NBOH does not affect reversal learning in mice . Behavioural Pharmacology . 32 . 5 . 448–452 . August 2021 . 33595957 . 10.1097/FBP.0000000000000626 . 231953516 .
  24. Hori A, Nishida T, Takashiba S, Kubota S, Takigawa M . Regulatory mechanism of CCN2 production by serotonin (5-HT) via 5-HT2A and 5-HT2B receptors in chondrocytes . PLOS ONE . 12 . 11 . e0188014 . 2017-11-16 . 29145495 . 5690650 . 10.1371/journal.pone.0188014 . free . 2017PLoSO..1288014H .
  25. Hagsäter SM, Pettersson R, Pettersson C, Atanasovski D, Näslund J, Eriksson E . A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear . The International Journal of Neuropsychopharmacology . 24 . 9 . 749–757 . September 2021 . 34228806 . 8453278 . 10.1093/ijnp/pyab040 . free .
  26. Breusova K, Ernstsen KG, Palner M, Linnet K, Kristensen JL, Kretschmann AC . A quantitative method for the selective 5-HT2A agonist 25CN-NBOH in rat plasma and brain . Journal of Pharmaceutical and Biomedical Analysis . 199 . 114016 . May 2021 . 33784574 . 10.1016/j.jpba.2021.114016 . 232431316 .
  27. Märcher Rørsted E, Jensen AA, Kristensen JL . 25CN-NBOH: A Selective Agonist for in vitro and in vivo Investigations of the Serotonin 2A Receptor . ChemMedChem . 16 . 21 . 3263–3270 . November 2021 . 34288515 . 10.1002/cmdc.202100395 . 236157499 .
  28. Nelson DL, Lucaites VL, Wainscott DB, Glennon RA . 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 . January 1999 . 9933142 . 10.1007/PL00005315 . 20150858 .
  29. Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DE . 6 . 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 . January 2013 . 23336049 . 3547484 . 10.1021/cn3000668 .
  30. Web site: September 2015 . 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 . Hungarian .

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