2,5-Dimethoxy-4-tert-butylamphetamine

vanc 6 DOTB DOtB structure.svg skin-invert-image 225px Oral Serotonin receptor modulator; Serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor modulator None 42456-77-9 correct CAS 12262514 10440072 8317 2,5-Dimethoxy-4-tert-butylamphetamine; DOTB; DOtBu; 4-tert-Butyl-2,5-dimethoxyamphetamine 1-(4-tert-butyl-2,5-dimethoxyphenyl)propan-2-amine 15 25 1 2 CC(CC1=CC(=C(C=C1OC)C(C)(C)C)OC)N 1S/C15H25NO2/c1-10(16)7-11-8-14(18-6)12(15(2,3)4)9-13(11)17-5/h8-10H,7,16H2,1-6H3 RUAUPNFNQOGIFF-UHFFFAOYSA-N 2,5-Dimethoxy-4-tert-butylamphetamine (DOTB or DOtBu) is a non-hallucinogenic serotonin receptor modulator of the phenethylamine, amphetamine, and DOx families. Nichols DE Structure–activity relationships of serotonin 5-HT2A agonists Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1 5 2012 2190-460X 10.1002/wmts.42 free 559–579 A comparison of two isomeric 4-butyl groups in this series (Figure [19]) revealed that 2,5-dimethoxy-4-isobutylamphetamine 44 retained significant activity in a drug discrimination task, in rats trained to discriminate LSD from saline, whereas the 2-butyl homolog was about one third less potent than the isobutyl and also failed to produce full substitution in the rats. [...] FIGURE 19 | Potential 5-HT2A (5-hydroxytryptamine) receptor agonists with an isomeric 4-butyl ring substituent. [...] Nichols DE Chemistry and Structure-Activity Relationships of Psychedelics Current Topics in Behavioral Neurosciences 36 1–43 2018 28401524 10.1007/7854_2017_475 978-3-662-55878-2 If the 4-substituent is an alkyl group, branching adjacent to the aromatic ring is not tolerated. For example, 2,5-dimethoxy-4-isobutylamphetamine 46 (DOIB) demonstrated significant activity in a rat drug discrimination task, in animals trained to discriminate LSD from saline. DOIB had only about one-third the activity of DOM in humans, with a dose in the 10 to 15 mg range (Shulgin and Shulgin 1991). By contrast, the 2-butyl homolog was about one-third less potent, but also failed to produce full substitution in the rats. The active oral dose in man is reported to be 25–30 mg (Shulgin and Shulgin 1991). [...] Large bulky alkyl groups at the 4-position, such as isopropyl or tert-butyl, lead to inactive compounds (Glennon et al. 1981, 1982a; Glennon and Rosecrans 1982; Oberlender et al. 1984). Not surprisingly, therefore, aryl groups attached at the 4-position also gave antagonists, generally with low affinity (Trachsel et al. 2009). Interestingly, however, when a 3-phenylpropyl substituent was introduced at this position, the compound was reported to be a weak partial agonist (Dowd et al. 2000). Shulgin AT, Shulgin A #63 DOBU 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE https://erowid.org/library/books_online/pihkal/pihkal063.shtml PiHKAL: A Chemical Love Story 1991 Transform Press 1st Berkeley, CA 978-0-9630096-0-9 25627628 https://books.google.com/books?id=O8AdHBGybpcC The last of the butyl isomers, the tert-butyl compound, was made from a much more obvious starting material. This is the commercially available tert-butyl hydroquinone. It was methylated in sodium hydroxide with methyl iodide, and then carried through the above sequence (benzaldehyde. mp 124 °C from cyclohexane, nitrostyrene, yellow crystals from methanol, mp 95-96.5 °C, and lithium aluminum hydride reduction) to give 2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp 168 °C). Rats trained in a process called the Sidman Avoidance Schedule gave behavior that suggested that DOTB had no activity at all, and in human trials, doses of up to 25 milligrams were totally without effect. Shulgin A, Manning T, Daley PF #60. DOM 118–129 https://archive.org/details/shulgin-index-vol-1/page/118/mode/1up The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds Transform Press Berkeley, CA 1 2011 978-0-9630096-3-0 709667010 DOM, DOIB, and DOSB were compared in discrimination studies based on training with LSD (Oberlender et al., 1984). [...] Homologues: [...] DOIB: [...] Ref: (17-20) [...] (17) Animal discrimination studies based on LSD (Oberlender et al., 1984). (18) Synthesis (Oberlender et al., 1984). (19) Serotonin receptor affinities determined in isolated rat fundus preparation, and studies in rats trained to discriminate 5-MeO-DMT from saline (Glennon et al., 1981b). Use and effects According to Alexander Shulgin and colleagues, DOTB has been found to be inactive in humans at doses of up to 25mg orally. Nichols DE, Glennon RA 1984 Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens Jacobs BL Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives 95–142 Raven Press New York 978-0-89004-990-7 10324237 https://books.google.com/books?id=EdpsAAAAMAAJ&pg=PA95 https://bitnest.netfirms.com/external/Books/HallucinogensNBCP95 Shulgin AT Basic Pharmacology and Effects 67–137 Laing RR Hallucinogens: A Forensic Drug Handbook Elsevier Science Forensic Drug Handbook Series 2003 978-0-12-433951-4 https://books.google.com/books?id=l1DrqgobbcwC https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 1 February 2025 Jacob P, Shulgin AT Structure-activity relationships of the classic hallucinogens and their analogs NIDA Research Monograph 146 74–91 1994 8742795 https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 https://web.archive.org/web/20230815054333/https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 August 15, 2023 Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology Pharmacodynamics DOTB binds with high affinity to the serotonin 5-HT2 receptors, including to the serotonin 5-HT2A and 5-HT2C receptors and, to about a 10-fold lesser extent, to the serotonin 5-HT2B receptor. Nelson DL, Lucaites VL, Wainscott DB, Glennon RA 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 January 1999 9933142 10.1007/pl00005315 Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors Frontiers in Pharmacology 14 1101290 2023 36762110 9902381 10.3389/fphar.2023.1101290 free Seggel MR, Yousif MY, Lyon RA, Titeler M, Roth BL, Suba EA, Glennon RA A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors Journal of Medicinal Chemistry 33 3 1032–1036 March 1990 2308135 10.1021/jm00165a023 It has been found to act as a partial agonist of the serotonin 5-HT2A receptor, with an intrinsic efficacy of about 30% for phosphatidylinositol hydrolysis and about half of the efficacy of (R)-DOB. Glennon RA, Teitler M, Sanders-Bush E Hallucinogens and serotonergic mechanisms NIDA Res Monogr 119 131–135 1992 1435968 https://archives.nida.nih.gov/sites/default/files/monograph119.pdf#page=161 https://web.archive.org/web/20230805002808/https://archives.nida.nih.gov/sites/default/files/monograph119.pdf#page=161 August 5, 2023 DOTB has also been assessed and found to act as a partial agonist of the serotonin 5-HT2B receptor (Emax 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. Glennon RA, Young R, Rosecrans JA A comparison of the behavioral effects of DOM homologs Pharmacol Biochem Behav 16 4 557–559 April 1982 7071089 10.1016/0091-3057(82)90414-2 Glennon RA Stimulus properties of hallucinogenic phenalkylamines and related designer drugs: formulation of structure-activity relationships NIDA Res Monogr 94 43–67 1989 2575229 https://archives.nida.nih.gov/sites/default/files/monograph94.pdf#page=54 https://web.archive.org/web/20230511144224/https://archives.nida.nih.gov/sites/default/files/monograph94.pdf#page=54 May 11, 2023 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-HT2A receptor. Glennon RA, Seggel MR Interaction of Phenylisopropylamines with Central 5-HT2 Receptors: Analysis by Quantitative Structure—Activity Relationships Probing Bioactive Mechanisms American Chemical Society Washington, DC 413 14 November 1989 978-0-8412-1702-7 10.1021/bk-1989-0413.ch018 264–280 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. Halberstadt AL, Powell SB, Geyer MA Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice Neuropharmacology 70 218–227 July 2013 23376711 3934507 10.1016/j.neuropharm.2013.01.014 It did still produce hyperthermia in rabbits similarly to other DOx drugs, albeit with dramatically reduced potency. Brimblecombe RW, Pinder RM Phenylalkylamines and Their Derivatives 55–97 Hallucinogenic Agents 1975 Bristol Wright-Scientechnica https://bitnest.netfirms.com/external/Books/978-0-85608-011-1#page=33 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* [...] Chemistry Synthesis The chemical synthesis of DOTB has been described. Analogues 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. Oberlender RA Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens Purdue University Purdue e-Pubs May 1989 https://bitnest.netfirms.com/external/Theses/Oberlender1989 17 February 2025 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). 540px|thumb|left|class=skin-invert-image|DOIB, DOSB, and DOTB. History DOTB was first described in the scientific literature in 1974. Aldous FA, Barrass BC, Brewster K, Buxton DA, Green DM, Pinder RM, Rich P, Skeels M, Tutt KJ Structure-activity relationships in psychotomimetic phenylalkylamines Journal of Medicinal Chemistry 17 10 1100–1111 October 1974 4418757 10.1021/jm00256a016 Its psychoactive effects were first assessed and described by Alexander Shulgin in 1975. Shulgin AT, Dyer DC Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines Journal of Medicinal Chemistry 18 12 1201–1204 December 1975 1195275 10.1021/jm00246a006 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. Society and culture Legal status Canada DOTB is a controlled substance in Canada under phenethylamine blanket-ban language.Controlled Drugs and Substances Act Department of Justice Canada https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html 19 January 2026 See also DOx (psychedelics) 2C-tBu References External links DOTB - Isomer Design Category:5-HT2B agonists Category:DOx (psychedelics) Category:Non-hallucinogenic 5-HT2A receptor agonists Category:Serotonin receptor agonists Category:Tert-butyl compounds