2,5-Dimethoxy-4-sec-butylamphetamine

Last updated

DOSB
DOSB structure.png
Clinical data
Other names2,5-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
Routes of
administration 		Oral
Drug class Serotonin receptor agonist; Serotonergic psychedelic; Hallucinogen
Identifiers
  • 1-(4-butan-2-yl-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)
  • CCC(C)C1=C(C=C(C(=C1)OC)CC(C)N)OC
  • InChI=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
  • Key: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. [1] [2] [3] [4]

Contents

Effects

In humans, DOSB is active at doses of 25 to 30 mg orally. [3] Similarly to DOBU, it is said that there is a "strong stimulation factor, with real and long-lasting sleep disturbance". [3] In a subsequent publication however, Alexander Shulgin stated that DOSB was inactive at 25 mg orally. [4] David E. Nichols also said that DOSB was inactive at up to 10 mg orally. [5]

Pharmacology

The affinity of DOSB for the rat serotonin 5-HT2 receptor was about 7.8 nM. [1] [2] [6] For comparison, the affinities of LSD and DOM in the same study were 6.31 nM and 18.6 nM, respectively. [6] DOSB substitutes for LSD in rodent drug discrimination tests, albeit much less potently than DOM (ED50 Tooltip median effective dose = 1.80 mg/kg versus 0.148 mg/kg, respectively; ~12-fold difference) and with only partial generalization (70% versus 99%, respectively). [1] [2] [3] [7] [6] However, in a subsequent study, full generalization was obtained. [6]

Chemistry

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. [4] [8] [9]

Some other notable analogues of DOSB include DOBU (n-butyl), DOIB (iso-butyl), and DOTB (sec-butyl). [1] [2] [10] [11] [5]

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

History

DOSB was first described in the scientific literature by 1984. [7] [5]

References

  1. 1 2 3 4 5 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 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. [...]
  2. 1 2 3 4 5 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). 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).
  3. 1 2 3 4 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 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.
  4. 1 2 3 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: [...] 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).
  5. 1 2 3 4 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. 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.
  6. 1 2 3 4 Oberlender R, Ramachandran PV, Johnson MP, Huang X, Nichols DE (September 1995). "Effect of a chiral 4-alkyl substituent in hallucinogenic amphetamines". Journal of Medicinal Chemistry. 38 (18): 3593–3601. doi:10.1021/jm00018a019. PMID   7658446.
  7. 1 2 Oberlender RA, Kothari PJ, Nichols DE, Zabik JE (June 1984). "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. doi:10.1021/jm00372a015. PMID   6737421.
  8. ↑ 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.
  9. ↑ 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).
  10. 1 2 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.
  11. 1 2 Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs". NIDA Research Monograph. 146: 74–91. PMID   8742795.
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