2,5-Dimethoxy-4-tert-butylamphetamine

Last updated

DOTB
DOTB structure.png
Clinical data
Other names2,5-Dimethoxy-4-tert-butylamphetamine; DOTB; DOtBu; 4-tert-Butyl-2,5-dimethoxyamphetamine
Routes of
administration 		Oral
Drug class Serotonin receptor modulator; Serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor modulator
Identifiers
  • 1-(4-tert-butyl-2,5-dimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C15H25NO2
Molar mass 251.370 g·mol−1
3D model (JSmol)
  • CC(CC1=CC(=C(C=C1OC)C(C)(C)C)OC)N
  • InChI=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
  • Key: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. [1] [2] [3] [4] It 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. [4] [5] [6]

Contents

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. [5] [7] [8] [9] 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. [10] [11] It has also been assessed and found to act as a partial agonist of the serotonin 5-HT2B receptor (Emax Tooltip maximal efficacy = 69%). [7]

The drug appeared to be inactive in animals in the conditioned avoidance test in rodents. [3] [12] Unlike DOM but similarly to DOAM, it did not substitute for 5-MeO-DMT in rodent drug discrimination tests. [6] 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. [11] Analogously to animal findings, DOTB was inactive in humans at oral doses of up to 25 mg. [3] [6] [13] [14] [15] On the other hand, it did still produce hyperthermia in rabbits similarly to other DOx drugs, albeit with dramatically reduced potency. [16] [12] [6]

Chemistry

Some other notable analogues of DOTB include DOBU (n-butyl), DOIB (iso-butyl), and DOSB (sec-butyl). [1] [2] [14] [15] [13]

DOIB, DOSB, and DOTB. DOIB,DOSBandDOTB.png
DOIB, DOSB, and DOTB.

History

DOTB was first described in the scientific literature by 1974. [16] Its psychoactive effects were first assessed and described by Alexander Shulgin in 1975. [6] [17]

References

  1. 1 2 3 Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi: 10.1002/wmts.42 . ISSN   2190-460X. 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. [...]
  2. 1 2 3 Nichols DE (2018). Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN   978-3-662-55878-2. PMID   28401524. 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).
  3. 1 2 3 Shulgin AT, Shulgin A (1991). "#63 DOBU 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN   978-0-9630096-0-9. OCLC   25627628. 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.
  4. 1 2 Shulgin A, Manning T, Daley PF (2011). "#60. DOM". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley, CA: Transform Press. pp. 118–129. ISBN   978-0-9630096-3-0. OCLC   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).
  5. 1 2 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. PMID   9933142.
  6. 1 2 3 4 5 Oberlender RA (May 1989). "Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens". Purdue e-Pubs. Purdue University. Retrieved 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).
  7. 1 2 Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M (2023). "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. doi: 10.3389/fphar.2023.1101290 . PMC   9902381 . PMID   36762110.
  8. ↑ Seggel MR, Yousif MY, Lyon RA, Titeler M, Roth BL, Suba EA, et al. (March 1990). "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. doi:10.1021/jm00165a023. PMID   2308135.
  9. ↑ Glennon RA, Seggel MR (14 November 1989). "Interaction of Phenylisopropylamines with Central 5-HT2 Receptors: Analysis by Quantitative Structure—Activity Relationships". Probing Bioactive Mechanisms. Vol. 413. Washington, DC: American Chemical Society. pp. 264–280. doi:10.1021/bk-1989-0413.ch018. ISBN   978-0-8412-1702-7.
  10. ↑ Glennon RA, Teitler M, Sanders-Bush E (1992). "Hallucinogens and serotonergic mechanisms" (PDF). NIDA Res Monogr. 119: 131–135. PMID   1435968.
  11. 1 2 Halberstadt AL, Powell SB, Geyer MA (July 2013). "Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice". Neuropharmacology. 70: 218–227. doi:10.1016/j.neuropharm.2013.01.014. PMC   3934507 . PMID   23376711.
  12. 1 2 Brimblecombe RW, Pinder RM (1975). "Phenylalkylamines and Their Derivatives". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 55–97. 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* [...]
  13. 1 2 3 Nichols DE, Glennon RA (1984). "Medicinal Chemistry and Structure-Activity Relationships of Hallucinogens". In Jacobs BL (ed.). Hallucinogens: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press. pp. 95–142. ISBN   978-0-89004-990-7. OCLC   10324237.
  14. 1 2 3 Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN   978-0-12-433951-4 . Retrieved 1 February 2025.
  15. 1 2 3 Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Research Monograph. 146: 74–91. PMID   8742795.
  16. 1 2 Aldous FA, Barrass BC, Brewster K, Buxton DA, Green DM, Pinder RM, et al. (October 1974). "Structure-activity relationships in psychotomimetic phenylalkylamines". Journal of Medicinal Chemistry. 17 (10): 1100–1111. doi:10.1021/jm00256a016. PMID   4418757.
  17. ↑ Shulgin AT, Dyer DC (December 1975). "Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines". Journal of Medicinal Chemistry. 18 (12): 1201–1204. doi:10.1021/jm00246a006. PMID   1195275. 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.
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