2,5-Dimethoxy-4-sec-butylamphetamine

{{DISPLAYTITLE:2,5-Dimethoxy-4-''sec''-butylamphetamine}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | drug_name = DOSB | image = DOsB structure.svg | image_class = skin-invert-image | width = 250px | caption =

| legal_status =

| IUPAC_name = 1-(4-butan-2-yl-2,5-dimethoxyphenyl)propan-2-amine | C=15 | H=25 | N=1 | O=2 | SMILES = CCC(C)C1=C(C=C(C(=C1)OC)CC(C)N)OC | StdInChI = 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 | StdInChIKey = 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.<ref name="Nichols2012">{{cite journal | vauthors = Nichols DE | title=Structure–activity relationships of serotonin 5-HT2A agonists | journal=Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | volume=1 | issue=5 | date=2012 | issn=2190-460X | doi=10.1002/wmts.42 | doi-access=free | pages=559–579 | quote=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 <nowiki>|</nowiki> Potential 5-HT2A (5-hydroxytryptamine) receptor agonists with an isomeric 4-butyl ring substituent. [...]}}</ref><ref name="Nichols2018">{{cite book | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = | quote = 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).}}</ref><ref name="PiHKAL">{{cite book | vauthors = Shulgin AT, Shulgin A | chapter = #63 DOBU 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE | pages = | chapter-url = https://erowid.org/library/books_online/pihkal/pihkal063.shtml | title = PiHKAL: A Chemical Love Story | date = 1991 | publisher = Transform Press | edition = 1st | location = Berkeley, CA | isbn = 978-0-9630096-0-9 | oclc = 25627628 | url = https://books.google.com/books?id=O8AdHBGybpcC | quote = 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. }}</ref><ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | chapter = #60. DOM | pages = 118–129 | chapter-url = https://archive.org/details/shulgin-index-vol-1/page/118/mode/1up | title = The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher = Transform Press | location = Berkeley, CA | volume = 1 | year = 2011 | isbn = 978-0-9630096-3-0 | oclc = 709667010 | quote = 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). }}</ref>

==Use and effects== In humans, DOSB is active at doses of 25 to 30{{nbsp}}mg orally.<ref name="PiHKAL" /> Similarly to DOBU, it is said that there is a "strong stimulation factor, with real and long-lasting sleep disturbance".<ref name="PiHKAL" /> In a subsequent publication however, Alexander Shulgin stated that DOSB was inactive at 25{{nbsp}}mg orally.<ref name="ShulginManningDaley2011" /> David E. Nichols also said that DOSB was inactive at up to 10{{nbsp}}mg orally.<ref name="NicholsGlennon1984" />

==Interactions== {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

==Pharmacology== ===Pharmacodynamics=== The affinity of DOSB for the rat serotonin 5-HT<sub>2</sub> receptor was about 7.8{{nbsp}}nM.<ref name="Nichols2012" /><ref name="Nichols2018" /><ref name="OberlenderRamachandranJohnson1995" /> For comparison, the affinities of LSD and DOM in the same study were 6.31{{nbsp}}nM and 18.6{{nbsp}}nM, respectively.<ref name="OberlenderRamachandranJohnson1995" /> DOSB substitutes for LSD in rodent drug discrimination tests, albeit much less potently than DOM ({{Abbrlink|ED<sub>50</sub>|median effective dose}} = 1.80{{nbsp}}mg/kg versus 0.148{{nbsp}}mg/kg, respectively; ~12-fold difference) and with only partial generalization (70% versus 99%, respectively).<ref name="Nichols2012" /><ref name="Nichols2018" /><ref name="PiHKAL" /><ref name="OberlenderKothariNichols1984">{{cite journal | vauthors = Oberlender RA, Kothari PJ, Nichols DE, Zabik JE | title = 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 = Journal of Medicinal Chemistry | volume = 27 | issue = 6 | pages = 788–792 | date = June 1984 | pmid = 6737421 | doi = 10.1021/jm00372a015 }}</ref><ref name="OberlenderRamachandranJohnson1995">{{cite journal | vauthors = Oberlender R, Ramachandran PV, Johnson MP, Huang X, Nichols DE | title = Effect of a chiral 4-alkyl substituent in hallucinogenic amphetamines | journal = Journal of Medicinal Chemistry | volume = 38 | issue = 18 | pages = 3593–3601 | date = September 1995 | pmid = 7658446 | doi = 10.1021/jm00018a019 }}</ref> However, in a subsequent study, full generalization was obtained.<ref name="OberlenderRamachandranJohnson1995" />

==Chemistry== ===Synthesis=== The chemical synthesis of DOSB has been described.<ref name="PiHKAL" />

===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.<ref name="ShulginManningDaley2011" /><ref name="NelsonLucaitesWainscott1999">{{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 }}</ref><ref name="Oberlender1989">{{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).}}</ref>

Some other notable analogues of DOSB include DOBU (''n''-butyl), DOIB (''iso''-butyl), and DOTB (''sec''-butyl).<ref name="Nichols2012" /><ref name="Nichols2018" /><ref name="Shulgin2003">{{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}}</ref><ref name="JacobShulgin1994">{{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 = }}</ref><ref name="NicholsGlennon1984">{{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 | quote = 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.}}</ref>

==History== DOSB was first described in the scientific literature by David E. Nichols and colleagues by 1984.<ref name="OberlenderKothariNichols1984" /><ref name="NicholsGlennon1984" />

==Society and culture== ===Legal status=== ====Canada==== DOSB is a controlled substance in Canada under phenethylamine blanket-ban language.<ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act | website=Department of Justice Canada | url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html | access-date=19 January 2026}}</ref>

==See also== * DOx (psychedelics)

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/237 DOSB - Isomer Design]

Category:David E. Nichols Category:DOx (psychedelics) Category:Psychedelic phenethylamines Category:Sec-Butyl compounds Category:Serotonin receptor agonists