DOI-NBOMe

{{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | drug_name = | image = DOI-NBOMe.svg | image_class = skin-invert-image | width = 250px | image2 = DOI-NBOMe ball-and-stick structure.png | image_class2 = bg-transparent | width2 = 250px

<!-- Clinical data --> | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = | licence_EU = | DailyMedID = | licence_US = | pregnancy_AU = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = | class = Non-hallucinogenic serotonin 5-HT_2A receptor agonist | ATC_prefix = None | ATC_suffix =

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<!-- Identifiers --> | CAS_number = | CAS_supplemental = | PubChem = 169776666 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID = | UNII = | KEGG = | ChEBI = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = A1ELA | synonyms = NBOMe-DOI; ''N''-(2-Methoxybenzyl)-4-iodo-2,5-dimethoxyamphetamine; 4-Iodo-2,5-dimethoxy-''N''-(2-methoxybenzyl)amphetamine

<!-- Chemical data --> | IUPAC_name = 1-(4-iodo-2,5-dimethoxyphenyl)-''N''-[(2-methoxyphenyl)methyl]propan-2-amine | C=19 | H=24 | I=1 | N=1 | O=3 | SMILES = CC(CC1=CC(=C(C=C1OC)I)OC)NCC2=CC=CC=C2OC | StdInChI = 1S/C19H24INO3/c1-13(21-12-14-7-5-6-8-17(14)22-2)9-15-10-19(24-4)16(20)11-18(15)23-3/h5-8,10-11,13,21H,9,12H2,1-4H3 | StdInChIKey = XRQNUXKKHOVYIR-UHFFFAOYSA-N }}

'''DOI-NBOMe''', or '''NBOMe-DOI''', also known as '''''N''-(2-methoxybenzyl)-4-iodo-2,5-dimethoxyamphetamine''', is a non-hallucinogenic serotonin 5-HT_2A receptor biased agonist of the phenethylamine, DOx, and 25-NB (NBOMe) families.<ref name="Trachsel_2013">{{cite book | vauthors = Trachsel D, Lehmann D, Enzensperger C | title = Phenethylamine: von der Struktur zur Funktion | location = Solothurn | pages = 837–838,841 | year = 2013 | trans-title = Phenethylamines: From Structure to Function | edition = 1 | publisher = Nachtschatten-Verlag | series = Nachtschatten-Science | isbn = 978-3-03788-700-4 | oclc = 858805226 | url = https://books.google.com/books?id=-Us1kgEACAAJ | language = de }}</ref><ref name="Halberstadt_2017">{{cite journal | vauthors = Halberstadt AL | title = Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens | journal = Current Topics in Behavioral Neurosciences | volume = 32 | pages = 283–311 | date = 2017 | pmid = 28097528 | doi = 10.1007/7854_2016_64 | isbn = 978-3-319-52442-9 | quote = Differences exist between the structure–activity relationships (SAR) of hallucinogens in the NBOMe and phenylalkylamine classes. First, there is a difference in the effect of α-methyl substitution. Compared to their α-desmethyl congeners, phenylisopropylamine hallucinogens have higher intrinsic activities at 5-HT2A, which is thought to be the reason why the phenylisopropylamines have higher potency in vivo [41, 42]. With NBOMes, however, the presence of an α-methyl group reduces intrinsic activity and 5-HT2A affinity [23]. According to Braden et al., adding an α-methyl group to 25I-NBOMe reduced its efficacy (Emax) from 78% to 43% and produced a 12-fold reduction of affinity for rat 5-HT2A receptors labeled with [125I]DOI. | doi-access = free }}</ref><ref name="Braden_2007" /><ref name="Braden_2006">{{cite journal | vauthors = Braden MR, Parrish JC, Naylor JC, Nichols DE | title = Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists | journal = Molecular Pharmacology | volume = 70 | issue = 6 | pages = 1956–1964 | date = December 2006 | pmid = 17000863 | doi = 10.1124/mol.106.028720 }}</ref><ref name="Heim_2003">{{cite web | vauthors = Heim R | title = Synthese und Pharmakologie potenter 5-HT_2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur. Entwicklung eines neuen Struktur-Wirkungskonzepts. | date = 25 March 2003 | trans-title = Synthesis and pharmacology of potent 5-HT2A receptor agonists with an N-2-methoxybenzyl partial structure. Development of a new structure-activity concept. | url = http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000001221 | publisher = diss.fu-berlin.de | language = German | access-date = 2013-05-10 | archive-date = 2012-04-16 | archive-url = https://web.archive.org/web/20120416040543/http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000001221 | url-status = live }}</ref> It is the ''N''-(2-methoxybenzyl) derivative of DOI and the amphetamine (i.e., α-methyl) analogue of 25I-NBOMe.<ref name="Braden_2006" /><ref name="Braden_2007" /><ref name="Heim_2003" />

==Pharmacology== ===Pharmacodynamics=== DOI-NBOMe is a potent serotonin 5-HT_2A receptor partial agonist, with an affinity (K_i) of 0.78 to 1.08{{nbsp}}nM, an {{Abbrlink|EC₅₀|half-maximal effective concentration}} of 36.1{{nbsp}}nM, and an {{Abbrlink|E_max|half-maximal effective concentration}} of 43% in the employed assay.<ref name="Braden_2006" /><ref name="Braden_2007" /> As an agonist of the serotonin 5-HT_2A receptor, DOI-NBOMe had about half the affinity and potency of DOI and a little more than half the efficacy in comparison ''in vitro'' (with DOI having a K_i of 0.58–0.64{{nbsp}}nM, an {{Abbr|EC₅₀|half-maximal effective concentration}} of 19.2{{nbsp}}nM, and an {{Abbr|E_max|half-maximal effective concentration}} of 77%).<ref name="Braden_2006" /><ref name="Braden_2007" /> Compared to 25I-NBOMe, the corresponding NBOMe analogue of 2C-I, DOI-NBOMe had about 14.4-fold lower potency as a serotonin 5-HT_2A receptor agonist and slightly more than half the activational efficacy.<ref name="Braden_2006" /><ref name="Braden_2007" /> Whereas the potency of 2Cs can be dramatically increased by ''N''-(2-methoxybenzyl) substitution, this has not been the case with the DOx series of psychedelics, where activity has been negatively impacted.<ref name="Halberstadt_2017" /><ref name="Braden_2006" /><ref name="Braden_2007" /><ref name="Heim_2003" /><ref name="Silva_2009">{{Cite thesis | vauthors = Silva M | title = Theoretical study of the interaction of agonists with the 5-HT2A receptor | year = 2009 | type = PhD. | url = http://epub.uni-regensburg.de/12119/ | publisher = Universität Regensburg | quote = Table 5.1: Agonistic potency (pEC50) and intrinsic activity (Emax) of 5-HT2AR partial agonistic arylethylamines (indole, methoxybenzene and quinazolinedione derivatives) used in the study. [...] [Compound] 234 [...] }}</ref><ref name="Silva_2011">{{cite journal | vauthors = Silva ME, Heim R, Strasser A, Elz S, Dove S | title = Theoretical studies on the interaction of partial agonists with the 5-HT2A receptor | journal = Journal of Computer-aided Molecular Design | volume = 25 | issue = 1 | pages = 51–66 | date = January 2011 | pmid = 21088982 | doi = 10.1007/s10822-010-9400-2 | bibcode = 2011JCAMD..25...51S | quote = Table 1 Structure, agonistic potency (pEC50) and efficacy (Emax) of r5-HT2AR partial agonistic arylethylamines [...] [Compound] 25 [...] On average, methyl groups in a-position of the ethyl side chain decrease activity. However, the effect of a-Me depends on the nature of the amino group: if one considers the pEC50 values and residuals (see Table 1), it becomes obvious that the methyl branch is favourable in primary amines (cpds. 11 and 12) and unfavourable in secondary benzylamines (cpds. 17 and 25). This different behavior may be simply due to a potential interaction of the a-Me group with the receptor which is not possible in the case of a bulky RN moiety because of restricted degrees of freedom for fit. A methyl group as part of a tertiary amine strongly lowers activity. }}</ref>

Besides the serotonin 5-HT_2A receptor, DOI-NBOMe has also been shown to bind to the serotonin 5-HT_2C receptor, with an affinity (K_i) of 21.0{{nbsp}}nM.<ref name="Braden_2007">{{cite thesis | vauthors = Braden MR | title = Towards a biophysical understanding of hallucinogen action | date = 2007 | degree = Ph.D. | publisher = Purdue University | id = {{ProQuest | 304838368}}|url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=9a30faca37ad48466b87a192ccd542401dc24012|quote=With the exceptions of the N-(2-methoxy)benzyl analogue of DOI (DOI-NBOMe), and the N-(2-napthyl)methyl analogue of 25I (25I-NNap) all N-arylmethyl analogues of phenylalkylamines followed this trend of increased binding affinity at the rat 5-HT2A receptor. [...] All compounds tested were relatively potent agonists at the cloned rat 5-HT2A receptor and possessed robust intrinsic activities, with the exception of DOI-NBOMe, 25I-NB 25I-NNap, and 25I-NBF, which were weak partial agonists. [...] Table 4.3 Effect of N-alkyl or N-aryl phenylalkylamine substitution on binding and functional activity at the rat 5-HT2A receptor. [...] Table A.1 Binding affinities at wild type human and rat 5-HT receptors. [...]}}</ref> This was about 33-fold lower than the affinity of DOI.<ref name="Braden_2007" /> As such, DOI-NBOMe appears to show increased selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor compared to DOI.<ref name="Braden_2007" /> For comparison, 25I-NBOMe had increased affinities for both the serotonin 5-HT_2A receptor and to a lesser extent the serotonin 5-HT_2C receptor compared to 2C-I.<ref name="Braden_2007" />

Subsequent to its earlier discovery and characterization, DOI-NBOMe was found to be a biased agonist of the serotonin 5-HT_2A receptor, with robust G_q activation comparable to DOI but minor efficacy on G_i signaling.<ref name="XuWangYu2026">{{cite journal | vauthors = Xu Z, Wang H, Yu J, Deng Y, Tian X, Ni R, Xia F, Yang L, Xu C, Zhang L, Luo R, Chen P, Zhang X, Liu Y, Hou J, Zhang M, Chen S, Su L, Sun H, He Y, Chen D, Chen X, Miao Z, Xie J, Liu X, Zhao J, Ke B, Tian X, Zeng L, Zhang L, Tang X, Yang S, Liu J, Wang X, Yan W, Shao Z | title = Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling | journal = Nature | volume = | issue = | pages = | date = January 2026 | pmid = 41606342 | doi = 10.1038/s41586-025-10061-7 | url = }}</ref> In addition, it was selective for the serotonin 5-HT_2A receptor, with much less or no agonism of the 5-HT_1A, 5-HT_2B, or 5-HT_2C receptors.<ref name="XuWangYu2026" /> The {{Abbr|EC₅₀|half-maximal effective concentration}} ({{Abbr|E_max|maximal efficacy}}) values were 10{{nbsp}}nM (103%) at the serotonin 5-HT_2A receptor (G_q) and 603{{nbsp}}nM (145%) at the serotonin 5-HT_2C receptor.<ref name="XuWangYu2026" /> Values for G_q, G_i, and β-arrestin2 signaling at the serotonin 5-HT_2A receptor were also reported.<ref name="XuWangYu2026" /> DOI-NBOMe failed to produce the head-twitch response in rodents.<ref name="XuWangYu2026" /> Moreover, DOI-NBOMe antagonized the head-twitch response induced by DOI or LSD.<ref name="XuWangYu2026" /> The drug was found to produce rapid and sustained antidepressant-like effects in the forced swim test (FST) in rodents.<ref name="XuWangYu2026" /> In addition, it produced sustained anxiolytic-like effects in the marble-burying test.<ref name="XuWangYu2026" /> It was concluded that serotonin 5-HT_2A receptor G_i signaling and not G_q signaling is involved in the psychedelic-like effects of serotonergic psychedelics.<ref name="XuWangYu2026" />

==Chemistry== ===Synthesis=== The chemical synthesis of DOI-NBOMe has been described.<ref name="XuWangYu2026" />

===Analogues=== Analogues of DOI-NBOMe include DOI, DOB-NBOMe, DOM-NBOMe, and 25I-NBOMe, among others.

==History== DOI-NBOMe was first described in the scientific literature by Ralf Heim by 2003.<ref name="Heim_2003" /> However, Heim only synthesized DOI-NBOMe without reporting its pharmacology.<ref name="Heim_2003" /> The pharmacological interactions of DOI-NBOMe were subsequently reported by Michael Braden and colleagues, from the lab of David E. Nichols, by 2006.<ref name="Braden_2006" /><ref name="Braden_2007" /> DOI-NBOMe was later further characterized in 2026.<ref name="XuWangYu2026" />

==See also== * 25-NB * DOx

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/5387 DOI-NBOMe - Isomer Design]

{{Serotonin receptor modulators}} {{Phenethylamines}}

Category:25-NB (psychedelics) Category:Biased ligands Category:David E. Nichols Category:DOx (psychedelics) Category:Iodobenzene derivatives Category:2-Methoxyphenyl compounds Category:Selective 5-HT2A receptor agonists