2,5-Dimethoxy-4-sec-butylamphetamine

vanc 6 DOSB DOsB structure.svg skin-invert-image 250px Oral Serotonin receptor agonist; Serotonergic psychedelic; Hallucinogen None 89556-71-8 146057 128843 332535 2,5-Dimethoxy-4-sec-butylamphetamine; 4-sec-Butyl-2,5-dimethoxyamphetamine; DOSB; DOSBu; 2,5-Dimethoxy-4-(2-butyl)amphetamine; 1-(2,5-dimethoxy-4-(2-butyl)phenyl)-2-aminopropane; 1-DBPAP 1-(4-butan-2-yl-2,5-dimethoxyphenyl)propan-2-amine 15 25 1 2 CCC(C)C1=C(C=C(C(=C1)OC)CC(C)N)OC 1S/C15H25NO2/c1-6-10(2)13-9-14(17-4)12(7-11(3)16)8-15(13)18-5/h8-11H,6-7,16H2,1-5H3 VEQUTPSVRQTUHR-UHFFFAOYSA-N 2,5-Dimethoxy-4-sec-butylamphetamine (DOSB or DOSBu), also known as 1-(2,5-dimethoxy-4-(2-butyl)phenyl)-2-aminopropane (1-DBPAP), is a 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 18) 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. Asymmetric synthesis of the two separate 2-butyl isomers, with either R or S stereochemistry in the 2-butyl group, was then carried out. Assessment of receptor affinities by displacement of [125I]DOI from rat frontal cortical homogenate revealed identical Ki values of 7.8 nM.70 Drug discrimination tests in LSD-trained rats showed, however, that the R isomer (45) was slightly more potent than the S (46) (ED50 of 3.1 vs 4.8 µmol, respectively) (Figure 19). This difference could reflect a slight difference in functional potency or intrinsic activity, but those were not examined. In general, however, the conclusion is that there is no chiral discrimination by the receptor in this region, and that branching in the 4-alkyl group, per se, is detrimental to the activity. [...] 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). In vitro examination of R and S stereochemistry in the 2-butyl group by displacement of [125I]DOI from rat frontal cortical homogenate revealed identical affinities (Ki values) of 7.8 nM for both isomers (Oberlender et al. 1995). Drug discrimination tests of the two isomers in LSD-trained rats revealed that the R isomer (47) was only slightly more potent than the S (48) (ED50 of 3.1 vs. 4.8 lmol, respectively). The conclusion is that there is no chiral discrimination by the receptor in the region of the 4-substituent, and that branching in the 4-alkyl group proximal to the aryl ring is detrimental to activity. [...] 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 isomer with the sec-butyl group was made in a somewhat similar manner, from 2,5-dimethoxyacetophenone. The addition of ethyl magnesium bromide gave an alcohol which with dehydration yielded a pair of dimethylstyrenes isomeric to the compound mentioned above. From there an identical sequence of steps (hydrogenation, benzaldehyde synthesis, nitrostyrene, and lithium aluminum hydride reduction) produced 2,5-dimethoxy-4-(1-methylpropyl)amphetamine hydrochloride (DOSB, mp 168–170 °C.). In the rat studies it was only a twelfth the potency of DOM, and in man the active dose is in the 25 to 30 milligram area. As with the normal butyl compound, there is a strong stimulation factor, with real and long-lasting sleep disturbance. 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: [...] DOSB: [...] Ref: (17,18,20-22) [...] (18) Synthesis (Oberlender et al., 1984). [...] (20) A comparison of steric properties with animal and human potency of several phenethylamines, tryptamines, and lysergide derivatives was made (Nichols, 1986a). (21) The sec-butyl R- and S-isomers were synthesized and compared as to serotonin receptor agonist activity (Oberlender et al., 1995). (22) Synthesis, physical properties described (Shulgin, 1970). Not orally active in humans at 25 mg (Shulgin and Shulgin, 1991). Use and effects In humans, DOSB is active at doses of 25 to 30mg orally. Similarly to DOBU, it is said that there is a "strong stimulation factor, with real and long-lasting sleep disturbance". In a subsequent publication however, Alexander Shulgin stated that DOSB was inactive at 25mg orally. David E. Nichols also said that DOSB was inactive at up to 10mg orally. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology Pharmacodynamics The affinity of DOSB for the rat serotonin 5-HT2 receptor was about 7.8nM. For comparison, the affinities of LSD and DOM in the same study were 6.31nM and 18.6nM, respectively. DOSB substitutes for LSD in rodent drug discrimination tests, albeit much less potently than DOM (ED50 median effective dose = 1.80mg/kg versus 0.148mg/kg, respectively; ~12-fold difference) and with only partial generalization (70% versus 99%, respectively). Oberlender RA, Kothari PJ, Nichols DE, Zabik JE Substituent branching in phenethylamine-type hallucinogens: a comparison of 1-[2,5-dimethoxy-4-(2-butyl)phenyl]-2-aminopropane and 1-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]-2-aminopropane Journal of Medicinal Chemistry 27 6 788–792 June 1984 6737421 10.1021/jm00372a015 Oberlender R, Ramachandran PV, Johnson MP, Huang X, Nichols DE Effect of a chiral 4-alkyl substituent in hallucinogenic amphetamines Journal of Medicinal Chemistry 38 18 3593–3601 September 1995 7658446 10.1021/jm00018a019 However, in a subsequent study, full generalization was obtained. Chemistry Synthesis The chemical synthesis of DOSB has been described. Analogues DOSB 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. 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 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 DOSB include DOBU (n-butyl), DOIB (iso-butyl), and DOTB (sec-butyl). 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 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 Branching in the 4-alkyl group is deleterious, at least if the branch is adjacent to the aromatic ring, as in such compounds as DOIPR, DOTB, and DOSB. Branching in the alkyl, ifit is more distal from the ring, may lead to compounds that retain high activity (e.g., 0018). These observations may be related to a possible requirement for the aromatic ring of the phenethylamines to closely approach the receptor surface, presumably to form a charge-transfer complex, as noted earlier. Bulky, branched alkyls attached to the ring would hinder this interaction (165). By contrast, branching further removed from the ring would not be expected to have as severe an effect. 540px|thumb|left|class=skin-invert-image|DOIB, DOSB, and DOTB. History DOSB was first described in the scientific literature by David E. Nichols and colleagues by 1984. Society and culture Legal status Canada DOSB 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) References External links DOSB - Isomer Design Category:David E. Nichols Category:DOx (psychedelics) Category:Psychedelic phenethylamines Category:Sec-Butyl compounds Category:Serotonin receptor agonists