A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to serotonin5-HT2 receptors andautoradiography.[8]
25CN-NBOH is notable as one of the mostselectiveagonists of theserotonin5-HT2A receptor yet discovered, with anaffinity (pKi) of 8.88 at the human serotonin 5-HT2A receptor, 100-fold selectivity for the serotonin 5-HT2A receptor over the serotonin5-HT2C receptor, and 46-fold selectivity for the serotonin 5-HT2A receptor over the serotonin5-HT2B receptor.[4][5][6][7] However, another study found that 25CN-NBOH only had around 25-fold selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2B and 5-HT2C receptors.[3][7] In any case, in 2020, 25CN-NBOH and the related drug(S,S)-DMBMPP were described as the most selective serotonin 5-HT2A receptor agonists discovered to date.[3]
25CN-NBOH was found to partially substitute forDOI indrug discrimination tests but was considerably weaker at inducing thehead-twitch response (HTR) in mice.[9][10] As with DOI, 25CN-NBOH has shown a biphasic orinverted U-shapeddose–response curve in terms of HTR induction.[9][11] In addition, as with many other psychedelics,tolerance andtachyphylaxis develop to the HTR induced by 25CN-NBOH.[11] A study 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."[11]
25CN-NBOH induces the HTRs also referred to as "wet dog shakes" (WDS) in rodents and the cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior has been investigated in detail.[12]
Additional in vivo investigations with this ligand has emerged.[13][14][15][16][17][18][19][20] Chronic administration in mice lead to desensitization of the 5-HT2AR (measured via HTR) and increased startle amplitude[21] whereas it does not effect reversal learning in mice.[22] 25CN-NBOH was shown to increase the production ofCTGF inchondrocytes.[23] In rats, 25CN-NBOH induce a reduction in conditioned fear that was countered by pretreatment with 5-HT2AR inverse agonist MDL100907.[24]
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.[25]
The tendency of the 4-cyano substitution to confer high 5-HT2A selectivity had previously been observed with DOCN,[29] 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 cyclized derivative2S,6S-DMBMPP ((2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine),[30] in binding assays, however it is also less complex to synthesize and has higher efficacy and selectivity in functional assays as apartial agonist of the 5-HT2A receptor.
^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.PMID32298690.S2CID215802376.
^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.PMID31693871.S2CID207831116.
^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.PMID35149433.S2CID246548173.
^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.PMID33095437.S2CID225052555.
^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.PMID33595957.S2CID231953516.
^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.PMID33784574.S2CID232431316.
^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.PMID34288515.S2CID236157499.
^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.PMID9933142.S2CID20150858.
