2,5-Dimethoxy-4-tert-butylamphetamine

According to Alexander Shulgin and colleagues, DOTB has been found to be inactive in humans at oral doses of up to 25{{nbsp}}mg.{{cite book | vauthors = Nichols DE, Glennon RA | date = 1984 | chapter = Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens | veditors = Jacobs BL | title = Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives | pages = 95–142 | publisher = Raven Press | location = New York | isbn = 978-0-89004-990-7 | oclc = 10324237 | url = https://books.google.com/books?id=EdpsAAAAMAAJ&pg=PA95 | chapter-url = https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95 }}{{cite book | vauthors = Shulgin AT | chapter=Basic Pharmacology and Effects | pages=67–137 | veditors = Laing RR | title=Hallucinogens: A Forensic Drug Handbook | publisher=Elsevier Science | series=Forensic Drug Handbook Series | year=2003 | isbn=978-0-12-433951-4 | url=https://books.google.com/books?id=l1DrqgobbcwC | chapter-url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 | access-date=1 February 2025}}{{cite journal | vauthors = Jacob P, Shulgin AT | title = Structure-activity relationships of the classic hallucinogens and their analogs | journal = NIDA Research Monograph | volume = 146 | issue = | pages = 74–91 | date = 1994 | pmid = 8742795 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 }}

DOTB binds with high affinity to the serotonin 5-HT₂ receptors, including to the serotonin 5-HT_2A and 5-HT_2C receptors and, to about a 10-fold lesser extent, to the serotonin 5-HT_2B receptor.{{cite journal | vauthors = Nelson DL, Lucaites VL, Wainscott DB, Glennon RA | title = Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 359 | issue = 1 | pages = 1–6 | date = January 1999 | pmid = 9933142 | doi = 10.1007/pl00005315 }}{{cite journal | vauthors = Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M | title = Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT_2A and 5-HT_2B serotonin receptors | journal = Frontiers in Pharmacology | volume = 14 | issue = | pages = 1101290 | date = 2023 | pmid = 36762110 | pmc = 9902381 | doi = 10.3389/fphar.2023.1101290 | doi-access = free }}{{cite journal | vauthors = Seggel MR, Yousif MY, Lyon RA, Titeler M, Roth BL, Suba EA, Glennon RA | title = A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 3 | pages = 1032–1036 | date = March 1990 | pmid = 2308135 | doi = 10.1021/jm00165a023 }} It has been found to act as a partial agonist of the serotonin 5-HT_2A receptor, with an intrinsic efficacy of about 30% for phosphatidylinositol hydrolysis and about half of the efficacy of (R)-DOB.{{cite journal | vauthors = Glennon RA, Teitler M, Sanders-Bush E | title = Hallucinogens and serotonergic mechanisms | journal = NIDA Res Monogr | volume = 119 | issue = | pages = 131–135 | date = 1992 | pmid = 1435968 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph119.pdf#page=161}} DOTB has also been assessed and found to act as a partial agonist of the serotonin 5-HT_2B receptor ({{Abbrlink|E_max|maximal efficacy}} = 69%).

The drug appeared to be inactive in animals in the conditioned avoidance test in rodents. DOTB only partially substituted for DOM in rodent drug discrimination tests (up to 70% responding, followed by disruption at higher doses) and with much lower potency than other DOx drugs.{{cite journal | vauthors = Glennon RA, Young R, Rosecrans JA | title = A comparison of the behavioral effects of DOM homologs | journal = Pharmacol Biochem Behav | volume = 16 | issue = 4 | pages = 557–559 | date = April 1982 | pmid = 7071089 | doi = 10.1016/0091-3057(82)90414-2 | url = }}{{cite journal | vauthors = Glennon RA | title = Stimulus properties of hallucinogenic phenalkylamines and related designer drugs: formulation of structure-activity relationships | journal = NIDA Res Monogr | volume = 94 | issue = | pages = 43–67 | date = 1989 | pmid = 2575229 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph94.pdf#page=54}} In combination with DOM, DOTB produced some antagonism of the stimulus generalization of DOM, suggesting action as a lower-efficacy partial agonist of the serotonin 5-HT_2A receptor.{{cite book | vauthors = Glennon RA, Seggel MR | chapter=Interaction of Phenylisopropylamines with Central 5-HT2 Receptors: Analysis by Quantitative Structure—Activity Relationships | title=Probing Bioactive Mechanisms | publisher=American Chemical Society | publication-place=Washington, DC | volume=413 | date=14 November 1989 | isbn=978-0-8412-1702-7 | doi=10.1021/bk-1989-0413.ch018 | pages=264–280 | url=https://bitnest.netfirms.com/external/10.1021/bk-1989-0413.ch018}} Unlike DOM but similarly to DOAM, DOTB did not substitute for 5-MeO-DMT in rodent drug discrimination tests. It also did not affect locomotor activity in rodents, again in contrast to other DOx drugs, though there were non-significant increases in locomotion at the highest assessed doses.{{cite journal | vauthors = Halberstadt AL, Powell SB, Geyer MA | title = Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice | journal = Neuropharmacology | volume = 70 | issue = | pages = 218–227 | date = July 2013 | pmid = 23376711 | pmc = 3934507 | doi = 10.1016/j.neuropharm.2013.01.014 | url = }} It did still produce hyperthermia in rabbits similarly to other DOx drugs, albeit with dramatically reduced potency.{{cite book | vauthors = Brimblecombe RW, Pinder RM | chapter = Phenylalkylamines and Their Derivatives | pages = 55–97 | title = Hallucinogenic Agents | date = 1975 | location = Bristol | publisher = Wright-Scientechnica | url = https://bitnest.netfirms.com/external/Books/978-0-85608-011-1#page=33 | quote = The N-propyl homologue of DOM (3.30) is even more potent than DOET in producing hyperthermia in the rabbit with true hallucinogenic profiles in open-field tests in rats and E.E.G. responses in cats, but branched alkyl groups such as isopropyl or tert-butyl have a profound deleterious effect (Table 3.5). Neither these compounds nor [DOC], which seems to be as potent as the 4-bromo analogue in animals, have yet been tested in man. [...] Table 3.5.—STRUCTURE–ACTIVITY RELATIONSHIPS IN ALKYL- AND HALO-AMPHETAMINES. RELATIVE POTENCIES* [...]}}

DOTB is part of the series of straight-chain and branched-chain 4-alkylated DOx drugs that also includes DOM, DOET, DOPR, DOBU, DOAM, and DOHx, among others.{{cite web | vauthors = Oberlender RA | title=Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens | publisher=Purdue University | website=Purdue e-Pubs | date=May 1989 | url=https://bitnest.netfirms.com/external/Theses/Oberlender1989 | access-date=17 February 2025 | quote=Table 7. Hallucinogenic potency of 4-alkyl-2,5-dimethoxyamphetamines.a [...] DOTB: [...] Hallucinogenic Potencyb: -c. [...] c this compound has not been established as hallucinogenic. [...] Within this homologous series, optimum activity is straight chain alkyl group, two and three carbons in length 1975). The potency increases by an order of magnitude as associated with a (Shulgin and Dyer, the 4-hydrogen of 2,5-DMA is replaced by a short alkyl chain, then decreases if the chain length exceeds four carbons. In addition, the lack of hallucinogenic activity for the tertiary butyl derivative, DOTB, suggested that branching of the 4-alkyl substituent was not tolerated. [...] In a study employing 5-MeO-DMT as the training drug in rats, DOTB and DOAM were distinguishable from this hallucinogen, while 2,5-DMA and DOM were not (Glennon et al., 1981). This was consistent with the studies described above. Surprisingly, however, stimulus generalization was not observed for DOET, DOPR, and DOBU (Glennon et al., 1981a). [...] Aldous et al. (1974) noted steric restrictions on the 4-substituent in the rabbit hyperthermia model since the 4-isopropyl derivative was more potent than the 4-tert-butyl analogue, DOTB. Additional studies with DOTB, which contains a more highly hindered benzylic carbon, indicate that hallucinogen-like activity may actually be abolished in man (Shulgin and Dyer, 1975) and drastically attenuated in animals (Glennon et al., 1982).}}

Some other notable analogues of DOTB include DOBU (n-butyl), DOIB (iso-butyl), and DOSB (sec-butyl).

Image:DOIB,DOSBandDOTB.png, DOSB, and DOTB.]]

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DOTB was first described in the scientific literature by 1974.{{cite journal | vauthors = Aldous FA, Barrass BC, Brewster K, Buxton DA, Green DM, Pinder RM, Rich P, Skeels M, Tutt KJ | title = Structure-activity relationships in psychotomimetic phenylalkylamines | journal = Journal of Medicinal Chemistry | volume = 17 | issue = 10 | pages = 1100–1111 | date = October 1974 | pmid = 4418757 | doi = 10.1021/jm00256a016 }} Its psychoactive effects were first assessed and described by Alexander Shulgin in 1975.{{cite journal | vauthors = Shulgin AT, Dyer DC | title = Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines | journal = Journal of Medicinal Chemistry | volume = 18 | issue = 12 | pages = 1201–1204 | date = December 1975 | pmid = 1195275 | doi = 10.1021/jm00246a006 | quote = The straight-chain homologous series from C0 to C5 as well as the 4-tert-butyl analog 6g have been prepared and have been quantitatively evaluated, both as serotonin agonists in in vitro preparations (employing sheep umbilical strip preparations8) and as psychotomimetics in vivo in man (utilizing the doubleconscious technique of assay1b,6). [...] Table I. Phenylisopropylamine Hydrochlorides 6. Physical and Pharmacological Properties [...] No.: 6g. R: t-C4H9. [...] Code: DOTB. ED25 * 10^-9 Mc: 7.4 (5.6–9.7). [...] Hallucn potencyf: n. [...] n This compound has not been established as being hallucinogenic. }}

• 2,5-Dimethoxy-4-tert-butylphenethylamine (2C-tBu)

{{Reflist}}

• [https://isomerdesign.com/pihkal/explore/236 DOTB - isomer design]

{{Serotonin receptor modulators}}

{{Phenethylamines}}

Category:5-HT2B agonists

Category:DOx (psychedelics)

Category:Non-hallucinogenic 5-HT2A receptor agonists

Category:Serotonin receptor agonists

Category:Tert-butyl compounds