25CN-NBOH

Last updated
25CN-NBOH
NBOH-2CCN structure.png
Clinical data
Other namesNBOH-2C-CN
Legal status
Legal status
Identifiers
  • 4-[2-[(2-hydroxyphenyl)methylamino]ethyl]-2,5-dimethoxybenzonitrile
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C18H20N2O3
Molar mass 312.369 g·mol−1
3D model (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]

Contents

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]

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.

(2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine SS9b structure.png
(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

Related Research Articles

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<span class="mw-page-title-main">25I-NBOH</span> Chemical compound

25I-NBOH is a derivative of the phenethylamine-derived hallucinogen 2C-I that was discovered in 2006 by a team at Purdue University.

<span class="mw-page-title-main">Quipazine</span> Chemical compound

Quipazine is a serotonergic drug of the piperazine group which is used in scientific research. It was originally intended as an antidepressant but never developed for medical use.

<span class="mw-page-title-main">25B-NBOMe</span> Chemical compound

25B-NBOMe is a derivative of the phenethylamine psychedelic 2C-B, discovered in 2004 by Ralf Heim at the Free University of Berlin. It acts as a potent full agonist for the 5HT2A receptor. Anecdotal reports from users suggest 25B-NBOMe to be an active hallucinogen at a dose of as little as 250–500 µg, making it a similar potency to other phenethylamine derived hallucinogens such as Bromo-DragonFLY. Duration of effects lasts about 12–16 hours, although the parent compound is rapidly cleared from the blood when used in the radiolabeled form in tracer doses. Recently, Custodio et al (2019) evaluated the potential involvement of dysregulated dopaminergic system, neuroadaptation, and brain wave changes which may contribute to the rewarding and reinforcing properties of 25B-NBOMe in rodents.

<span class="mw-page-title-main">25I-NBF</span> Chemical compound

25I-NBF is a derivative of the phenethylamine hallucinogen 2C-I, which acts as a highly potent partial agonist for the human 5-HT2A receptor, with bias towards the β-arrestin 2 coupled signalling pathway. It has been studied in its 11C radiolabelled form as a potential ligand for mapping the distribution of 5-HT2A receptors in the brain, using positron emission tomography (PET).

<span class="mw-page-title-main">25C-NBOMe</span> Psychedelic drug

25C-NBOMe is a psychedelic drug and derivative of the psychedelic phenethylamine 2C-C. 25C-NBOMe appeared on online vendor sites in 2010 but was not reported in the literature until 2011. It acts as a potent agonist of the 5HT2A receptor, and has been studied in its 11C radiolabelled form as a potential ligand for mapping the distribution of 5-HT2A receptors in the brain, using positron emission tomography (PET). Multiple deaths have occurred from usage of 25C-NBOMe due to the ease of accidental overdose. The long-term toxic effects of the drug have not been researched.

<span class="mw-page-title-main">25D-NBOMe</span> Chemical compound

25D-NBOMe is a derivative of the phenethylamine derived hallucinogen 2C-D. It acts in a similar manner to related compounds such as 25I-NBOMe, which is a potent agonist at the 5HT2A receptor. 25D-NBOMe has been sold as a street drug since 2010 and produces similar effects in humans to related compounds such as 25I-NBOMe and 25C-NBOMe. It was banned as a Temporary Class Drug in the UK on 10 June 2013 after concerns about its recreational use.

<span class="mw-page-title-main">25C-NBOH</span> Chemical compound

25-C-NBOH is a derivative of the phenethylamine derived hallucinogen 2C-C which has been sold as a designer drug. It has similar serotonin receptor affinity to the better-known compound 25C-NBOMe.

<span class="mw-page-title-main">DMBMPP</span> Chemical compound

DMBMPP, or 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine, is a 2-benzylpiperidine analog of the hallucinogenic N-benzylphenethylamine 25B-NBOMe and was discovered in 2011 by Jose Juncosa in the group of David E. Nichols at Purdue University. DMBMPP differs from 25B-NBOMe by incorporating the amine within a piperidine ring, making for a more rigid molecular structure than that of the open-chain 25B-NBOMe. The presence of the piperidine ring introduces two stereocenters, thus, four stereoisomers of this compound can be made.

<span class="mw-page-title-main">25CN-NBOMe</span> Chemical compound

25CN-NBOMe is a derivative of the phenethylamine 2C-CN. It acts in a similar manner to related compounds such as 25I-NBOMe, which are potent agonists at the 5HT2A receptor.

<span class="mw-page-title-main">25N-NBOMe</span> Chemical compound

25N-NBOMe is a derivative of the hallucinogen 2C-N. The pharmacological properties of 25N-NBOMe have not been described in the scientific literature, but it is believed to act in a similar manner to related compounds such as 25I-NBOMe and 25C-NBOMe, which are potent agonists at the 5HT2A receptor. 25N-NBOMe has been sold as a street drug and has only been described in the literature in terms of identification by forensic analysis.

<span class="mw-page-title-main">25E-NBOMe</span> Chemical compound

25E-NBOMe is a derivative of the phenethylamine 2C-E. It acts in a similar manner to related compounds such as 25I-NBOMe, which are potent agonists at the 5HT2A receptor. 25E-NBOMe has been sold as a drug and produces similar effects in humans to related compounds such as 25I-NBOMe and 25C-NBOMe.

<span class="mw-page-title-main">25B-NBOH</span> Chemical compound

25B-NBOH is a derivative of the phenethylamine derived hallucinogen 2C-B which has been sold as a designer drug. It acts as a potent serotonin receptor agonist with similar affinity to the better-known compound 25B-NBOMe at 5-HT2A and 5-HT2C receptors with pKis values of 8.3 and 9.4, respectively.

<span class="mw-page-title-main">25C-NBF</span> Chemical compound

25C-NBF is a derivative of the phenethylamine hallucinogen 2C-C, which acts as a highly potent partial agonist for the human 5-HT2A receptor.

<span class="mw-page-title-main">25G-NBOMe</span> Chemical compound

25G-NBOMe (NBOMe-2C-G) is a derivative of the phenethylamine hallucinogen 2C-G, which acts as a highly potent agonist for the human 5-HT2A receptor.

<span class="mw-page-title-main">25H-NBOMe</span> Chemical compound

25H-NBOMe (NBOMe-2C-H) is a derivative of the phenethylamine hallucinogen 2C-H, which acts as a highly potent full agonist for the human 5-HT2A receptor.

<span class="mw-page-title-main">25-NB</span> Family of serotonergic psychedelics

The 25-NB (25x-NBx) series, sometimes alternatively referred to as the NBOMe compounds, is a family of serotonergic psychedelics. They are substituted phenethylamines and were derived from the 2C family. They act as selective agonists of the serotonin 5-HT2A receptor. The 25-NB family is unique relative to other classes of psychedelics in that they are, generally speaking, extremely potent and relatively selective for the 5-HT2A receptor. Use of NBOMe series drugs has caused many deaths and hospitalisations since the drugs popularisation in the 2010s. This is primarily due to their high potency, unpredictable pharmacokinetics, and sellers passing off the compounds in the series as LSD.

<span class="mw-page-title-main">25E-NBOH</span> Chemical compound

25E-NBOH is a derivative of the phenethylamine derived hallucinogen 2C-E. It was first developed by Martin Hansen at the University of Copenhagen in 2010 as a brain imaging agent, but has subsequently been sold as a designer drug, first being identified in Brazil in 2018 on seized blotter paper, as well as in Slovenia. It acts as a potent serotonin receptor agonist with similar affinity to better-known compounds such as 25I-NBOMe at 5-HT2A and 5-HT2C receptors.

References

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  2. ↑ "CNS Medicinal Chemistry in the Kristensen Group". Department of Drug Design and Pharmacology. University of Copenhagen. 25 March 2019.
  3. ↑ 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): 243–249. doi:10.1021/cn400216u. PMC   3963123 . PMID   24397362.
  4. ↑ Jensen AA, McCorvy JD, Leth-Petersen S, Bundgaard C, Liebscher G, Kenakin TP, et al. (June 2017). "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. doi: 10.1124/jpet.117.239905 . 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. ↑ 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.
  7. ↑ Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, et al. (July 2020). "The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH". Biochemical Pharmacology. 177: 113979. doi:10.1016/j.bcp.2020.113979. PMID   32298690. S2CID   215802376.
  8. ↑ Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, et al. (September 2020). "Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor". Cell. 182 (6): 1574–1588.e19. doi:10.1016/j.cell.2020.08.024. PMC   7593816 . PMID   32946782.
  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): a–1524–4439. doi: 10.1055/a-1524-4439 . ISSN   2509-9396.
  10. ↑ 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): 1039–1047. doi:10.1007/s00213-014-3739-3. PMC   4339409 . PMID   25224567.
  11. ↑ 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.
  12. ↑ 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.
  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. 24 (11): 9463. doi: 10.3390/ijms24119463 . ISSN   1422-0067. PMC   10253917 . PMID   37298417.
  14. ↑ Harmon JL, Wills LP, McOmish CE, Demireva EY, Gingrich JA, Beeson CC, Schnellmann RG (April 2016). "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. doi:10.1124/jpet.115.228395. PMC   4809314 . PMID   26787771.
  15. ↑ Odland AU, Jessen L, Kristensen JL, Fitzpatrick CM, Andreasen JT (February 2021). "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.
  16. ↑ Yang GE, Tae HJ, Lee TK, Park YE, Cho JH, Kim DW, et al. (September 2019). "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 . PMC   6770640 . PMID   31540405.
  17. ↑ 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.
  18. ↑ Xing L, Kalebic N, Namba T, Vaid S, Wimberger P, Huttner WB (December 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.
  19. ↑ Elsilä LV, Korhonen N, Hyytiä P, Korpi ER (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 . PMC   7745734 . PMID   33343373.
  20. ↑ Liu X, Zhu H, Gao H, Tian X, Tan B, Su R (April 2022). "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. PMID   35149433. S2CID   246548173.
  21. ↑ Ilchibaeva T, Tsybko A, Zeug A, Müller FE, Guseva D, Bischoff S, et al. (August 2022). "Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes". Cells. 11 (15): 2384. doi: 10.3390/cells11152384 . PMC   9368268 . PMID   35954229.
  22. ↑ Tsybko AS, Ilchibaeva TV, Filimonova EA, Eremin DV, Popova NK, Naumenko VS (December 2020). "The Chronic Treatment With 5-HT2A 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.
  23. ↑ Odland AU, Kristensen JL, Andreasen JT (August 2021). "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. PMID   33595957. S2CID   231953516.
  24. ↑ 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.
  25. ↑ Hagsäter SM, Pettersson R, Pettersson C, Atanasovski D, Näslund J, Eriksson E (September 2021). "A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear". The International Journal of Neuropsychopharmacology. 24 (9): 749–757. doi: 10.1093/ijnp/pyab040 . PMC   8453278 . PMID   34228806.
  26. ↑ Breusova K, Ernstsen KG, Palner M, Linnet K, Kristensen JL, Kretschmann AC (May 2021). "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. PMID   33784574. S2CID   232431316.
  27. ↑ Märcher Rørsted E, Jensen AA, Kristensen JL (November 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. PMID   34288515. S2CID   236157499.
  28. ↑ 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.
  29. ↑ 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.
  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". www.legislation.gov.uk.
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