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-HT2Areceptor 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]
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]
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.
^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.
^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.