2,5-Dimethoxy-4-bromoamphetamine

Last updated

DOB
INN: Brolamfetamine
DOB-racemic-skeletal.svg
Chemical structure of (±)-DOB
DOB-3d-sticks.png
Ball-and-stick model of (R)-DOB
Clinical data
Other namesDOB; 4-Bromo-2,5-dimethoxyamphetamine; Brolamfetamine; Brolamphetamine; Bromo-DMA; 2,5-Dimethoxy-4-bromo-α-methylphenethylamine; 4-Bromo-2,5-dimethoxyphenyl-isopropylamine
Routes of
administration 		Oral [1] [2]
Drug class Serotonin 5-HT2 receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Onset of action 1–2 hours [1] [2]
Peak: 3–4 hours [1] [2]
Duration of action 18–36 hours [1] [2]
Identifiers
  • 1-(4-bromo-2,5-dimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
PubChemSID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C11H16BrNO2
Molar mass 274.158 g·mol−1
3D model (JSmol)
Melting point 63–65 °C (145–149 °F)
(207–208 °C hydrochloride)
  • CC(CC1=CC(=C(C=C1OC)Br)OC)N
  • InChI=1S/C11H16BrNO2/c1-7(13)4-8-5-11(15-3)9(12)6-10(8)14-2/h5-7H,4,13H2,1-3H3 Yes check.svgY
  • Key:FXMWUTGUCAKGQL-UHFFFAOYSA-N Yes check.svgY
   (verify)

2,5-Dimethoxy-4-bromoamphetamine (DOB), also known as brolamfetamine (INN Tooltip International Nonproprietary Name), [4] is a psychedelic drug of the phenethylamine, amphetamine, and DOx families. [1] [2] For many years, prior to the discovery of newer compounds, DOB was the most potent known phenethylamine psychedelic. [1] [2] It is taken orally. [1] [2]

Contents

The drug acts as an agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A receptor. [5] [6] Analogues of DOB include 2C-B, DOM, DOI, and Bromo-DragonFLY (DOB-DFLY), among others. [1] [7]

DOB was first synthesized by Alexander Shulgin in 1967 and was described by him and his colleagues in the scientific literature in 1971. [1] [8] Shulgin subsequently further described the effects of DOB in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). [1]

Use and effects

In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin lists DOB's dose as 1 to 3 mg orally and its duration as 18 to 30 hours. [1] In an earlier publication, he listed its dose as 2 to 3 mg for racemic DOB and 1 to 2 mg for the preferentially active (R)-DOB enantiomer. [1] In addition, he described the duration as being extremely long, with a gradual descent and baseline being achieved after 24 to 36 hours. [2] [1] The onset has been described as 1 to 2 hours, the time to peak as 3 or 4 hours, and a plateau occurring from 4 to 10 hours. [1] [2] Its onset is said to be relatively slow. [1]

The effects of DOB and (R)-DOB have been reported to include visual changes such as prismatic-colored rings around the moon and long-lasting "after-images" following seeing points of light, little visual distortion, an "incredible Moebius strip representation of reality at the intellectual level", rich fantasy, flashes of depersonalization, cosmic thinking, introspection, insights, intoxication, impairment, stimulation, brief lapses in attention or "little fugue states", body load, cramps, muscle tremors, and sleep disruption. [1] [2] At a low dose of 0.4 mg DOB, there was only enhanced visual perception, strengthening of colors, enriched emotional affect, a comfortable good feeling, and colorful and important dreams. [1]

(R)-DOB produced moderate effects at a dose of 0.5 mg and pronounced effects at 1.0 to 1.5 mg, whereas there were no effects with 0.5 mg (S)-DOB and only threshold and very slight effects with 1.0 mg (S)-DOB. [1] In relation to this, (R)-DOB is described as the more active enantiomer and (S)-DOB as much less active. [1] In one report, 1 mg (R)-DOB was described as not as strong as 2 mg DOB, suggesting that it is more potent than the racemate but is not double its potency and hence that (S)-DOB also contributes to the effects of the racemate. [1] (S)-DOB has never been tested up to fully active doses. [1]

Side effects

Side effects of DOB include body load, muscle tremors, muscle cramps, attention lapses described as "little fugue states", sleeping difficulties, and bizarre dreams. [1] [2]

Overdose

Overdose of DOB has been reported to produce cardiovascular symptoms and convulsions. [2] Excessively high doses of DOB may cause diffuse arterial spasm. [9] The vasospasm responded readily to intra-arterial and intravenous vasodilators, such as tolazoline. [9] A 35 mg overdose resulted in death, while a 75 mg overdose in a person with tolerance resulted in ergotism-like complications that required amputation. [2]

Interactions

DOB may interact synergistically with alcohol. [2]

Pharmacology

Pharmacodynamics

DOB activities
Target Affinity (Ki, nM)
5-HT1A 2,550–7,904
5-HT1B 941
5-HT1D 636
5-HT1E 556–1,427
5-HT1F ND
5-HT2A 0.6–81 (Ki)
0.52–50 (EC50 Tooltip half-maximal effective concentration)
57–105% (Emax Tooltip maximal efficacy)
5-HT2B 2.9–44 (Ki)
2.82–65 (EC50)
70–100% (Emax)
5-HT2C 1.3–78 (Ki)
0.25–102 (EC50)
58–112% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A 5,311
5-HT6 5,535
5-HT7 506
α1A, α1B >10,000
α1D ND
α2A 4,266
α2B 1,527
α2C 594
β1 2,425
β2 303
D1, D2 >10,000
D3 808
D4, D5 >10,000
H1 9,120
H2–H4 >10,000
M1, M2 >10,000
M3 1,152
M4, M5 >10,000
TAAR1 >1,000
I1 1,596
σ1 2,193
σ2 >10,000
SERT Tooltip Serotonin transporter8,538 (Ki)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
DAT Tooltip Dopamine transporter>10,000 (Ki)
MAO-A Tooltip Monoamine oxidase A100,000 (IC50 Tooltip half-maximal inhibitory concentration) (rat)
MAO-B Tooltip Monoamine oxidase B>100,000 (IC50) (rat)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [10] [11] [5] [12] [13] [14] [15] [16] [6] [17] [18]

DOB is a serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist. [5] [6] Its psychedelic effects are mediated by its agonistic properties at the 5-HT2A receptor. Due to its selectivity, DOB is often used in scientific research when studying the 5-HT2 receptor subfamily.

It is a very weak agonist of the human trace amine-associated receptor 1 (TAAR1) and a weak agonist of the rhesus monkey TAAR1. [18] [6] In contrast to the serotonin releasing agent MDMA, DOB does not produce protein kinase C (PKC) activation in the brains of rodents in vivo . [19] [20] The PKC activation by MDMA appears to be dependent on uptake by the serotonin transporter (SERT). [19] [20]

DOB has been found to reduce aggression in rats. [21] [22]

DOB is one of the most potent compounds in PiHKAL; while the active dose is similar to that of DOI, another psychedelic amphetamine, DOB has been shown to have a higher efficacy in triggering downstream effects mediated by serotonin 5-HT2 receptors. [23]

Chemistry

Tabs of DOB, confiscated by police in Concord, California in 2006. DOB blotters.jpg
Tabs of DOB, confiscated by police in Concord, California in 2006.

The full name of the chemical is 2,5-dimethoxy-4-bromoamphetamine. [1] DOB has a stereocenter and R-(−)-DOB is the eutomer. This is an important finding as it is suggestive that it is targeting different receptors relative to most other phenethylamines (e.g. MDMA) where the R-isomer serves as the distomer.

Synthesis

The chemical synthesis of DOB has been described. [1]

Analogues

Omission of the amphetamine related α-methyl leads to 2C-B, a compound that possesses a lower affinity for the 5-HT2A receptor and is a weaker receptor agonist.[ citation needed ] Other analogues of DOB include 4C-B, Bromo-DragonFLY, DOB-FLY, DOB-5-hemiFLY, and 25B-NBOMe, among others.

History

DOB was first synthesized by Alexander Shulgin in 1967. [1] It was first described in the scientific literature in a paper by Shulgin, Claudio Naranjo, and another colleague in 1971. [8] The INN Tooltip International Nonproprietary Name of DOB, brolamfetamine, was proposed and recommended by the World Health Organization (WHO) in 1986. [24] [25] This was the same year that the Multidisciplinary Association for Psychedelic Studies (MAPS) was founded. [26] DOB was registered with the WHO as a supposed "anorexic" (appetite suppressant). [27]

Society and culture

Internationally, DOB is a Schedule I substance under the Convention on Psychotropic Substances and the drug is legal only for medical, industrial or scientific purposes. [28]

Canada

Listed as a Schedule 1 as it is an analogue of amphetamine. [29]

Australia

DOB is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (February 2017). [30] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities. [30]

Russia

Schedule I, possession of at least 10 mg is a criminal offence. [31]

United Kingdom

DOB is a Class A drug in the United Kingdom under the Misuse of Drugs Act 1971.

United States

DOB is a Schedule I controlled substance under federal law in the United States. [7] It was scheduled in 1973. [32]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Erowid Online Books: "PiHKAL" - #62 DOB
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Shulgin A (1981). "Profiles of Psychedelic Drugs: 10. DOB". J Psychoactive Drugs. 13 (1): 99. doi:10.1080/02791072.1981.10471457. PMID   7277091. Archived from the original on 2025-07-12.
  3. ↑ Anvisa (24 July 2023). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  4. ↑ World Health Organization (2000). International Nonproprietary Names (INN) for Pharmaceutical Substances. World Health Organization. ISBN   978-0-11-986227-0.
  5. 1 2 3 Ray TS (February 2010). "Psychedelics and the human receptorome". PLOS ONE. 5 (2) e9019. Bibcode:2010PLoSO...5.9019R. doi: 10.1371/journal.pone.0009019 . PMC   2814854 . PMID   20126400.
  6. 1 2 3 4 Rudin D, Luethi D, Hoener MC, Liechti ME (2022). "Structure-activity Relation of Halogenated 2,5-Dimethoxyamphetamines Compared to their α‑Desmethyl (2C) Analogues". The FASEB Journal. 36 (S1) fasebj.2022.36.S1.R2121. doi: 10.1096/fasebj.2022.36.S1.R2121 . ISSN   0892-6638.
  7. 1 2 Shulgin A, Manning T, Daley PF (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley: Transform Press. p. 102. ISBN   978-0-9630096-3-0.
  8. 1 2 Shulgin AT, Sargent T, Naranjo C (1971). "4-Bromo-2,5-dimethoxyphenylisopropylamine, a new centrally active amphetamine analog". Pharmacology. 5 (2): 103–107. doi:10.1159/000136181. PMID   5570923. S2CID   46844380.
  9. 1 2 Bowen JS, Davis GB, Kearney TE, Bardin J (March 1983). "Diffuse vascular spasm associated with 4-bromo-2,5-dimethoxyamphetamine ingestion". JAMA. 249 (11): 1477–1479. doi:10.1001/jama.1983.03330350053028. PMID   6827726.
  10. ↑ "PDSP Database". UNC (in Zulu). Retrieved 2025-02-04.
  11. ↑ Liu T. "BindingDB BDBM50005257 (+)-2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine::(+)2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine::(+/-)2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine::(-)-2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine::(-)2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine::1-(4-bromo-2,5-dimethoxyphenyl)propan-2-amine::2-(2-Methoxy-phenyl)-1-methyl-ethylamine::2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine::2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine((-)-DOB)::2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine((R)-(-)-DOB)::2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine((S)-(+)-DOB)::2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine(DOB)::2-(4-Bromo-2,5-dimethoxy-phenyl)-1-methyl-ethylamine[R(-)DOB]::2-(5-Bromo-2,4-dimethoxy-phenyl)-1-methyl-ethylamine::Brolamfetamine::CHEMBL6607::DOB::Racemic DOB". BindingDB. Retrieved 2025-02-04.
  12. ↑ van Wijngaarden I, Soudijn W (1997). "5-HT2A, 5-HT2B and 5-HT2C receptor ligands". Pharmacochemistry Library. Vol. 27. Elsevier. pp. 161–197. doi:10.1016/s0165-7208(97)80013-x. ISBN   978-0-444-82041-9.
  13. ↑ Acuña-Castillo C, Villalobos C, Moya PR, Sáez P, Cassels BK, Huidobro-Toro JP (June 2002). "Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors". Br J Pharmacol. 136 (4): 510–519. doi:10.1038/sj.bjp.0704747. PMC   1573376 . PMID   12055129.
  14. ↑ 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.
  15. ↑ Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10 1590. doi: 10.3389/fphar.2019.01590 . PMC   6989591 . PMID   32038257.
  16. ↑ Scorza MC, Carrau C, Silveira R, Zapata-Torres G, Cassels BK, Reyes-Parada M (December 1997). "Monoamine oxidase inhibitory properties of some methoxylated and alkylthio amphetamine derivatives: structure-activity relationships". Biochem Pharmacol. 54 (12): 1361–1369. doi:10.1016/s0006-2952(97)00405-x. PMID   9393679.
  17. ↑ Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, et al. (December 2023). "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nat Commun. 14 (1) 8221. Bibcode:2023NatCo..14.8221W. doi:10.1038/s41467-023-44016-1. PMC   10724237 . PMID   38102107.
  18. 1 2 Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC   3236098 . PMID   22037049.
  19. 1 2 Kramer HK, Poblete JC, Azmitia EC (September 1997). "Activation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA) occurs through the stimulation of serotonin receptors and transporter". Neuropsychopharmacology. 17 (3): 117–129. doi:10.1016/S0893-133X(97)00026-2. PMID   9272479.
  20. 1 2 Kenneth H (1996). "Evidence for the involvement of the serotonin uptake transporter and the serotonin-2 receptor in the activation of protein kinase C (PKC) by substituted amphetamines in the adult rodent brain". ProQuest. New York University. Retrieved 2025-02-01. MDMA manifests its acute psychotropic and neurotoxic effects by releasing 5-HT from nerve endings. MDMA also shows a moderate agonist-like affinity (1.5-3.2 mM [(sic)]) for the central 5-HT2 receptor. Activation of this receptor stimulates the translocation/activation of protein kinase C (PKC) and the release of Ca2+ from intracellular sequestration sites. MDMA has already been shown to increase [Ca2+], and this may proceed through the activation of this receptor. [...] In vivo, both MDMA and PCA were found to produce a lasting translocation of [protein kinase C (PKC)] in the cortex and hippocampus of treated rats. Fluoxetine, a 5-HT uptake inhibitor, prevents PKC translocation, while ketanserin, a 5-HT2A antagonist, acts similarly but a diminished efficacy. Non-neurotoxic drugs like fluoxetine, DOB, and cocaine were devoid of MDMA's long-term PKC translocating abilities, and suggests that receptor stimulation alone is not the sole mechanism. In synaptosomes, MDMA was effective at producing PKC translocation by binding to the 5-HT uptake carner. This in vitro response [of] fluoxetine reverses this response and demonstrates that MDMA translocates PKC within the 5-HT nerve terminal.
  21. ↑ Morrison TR, Melloni RH (2014). "The role of serotonin, vasopressin, and serotonin/vasopressin interactions in aggressive behavior". Neuroscience of Aggression. Curr Top Behav Neurosci. Vol. 17. pp. 189–228. doi:10.1007/7854_2014_283. ISBN   978-3-662-44280-7. PMID   24496652. Another 5HT2A receptor partial agonist, DOB, has a marginally higher affinity for the 5HT2A receptor (in its low affinity state) than DOI (Roth et al. 1997), and in the water competition (WC) test it has been shown to block defensive aggression in rats. Interestingly, DOI also reduced the number of offensive aggressive behaviors (i.e., attacks, greater latency to first attack, shorter attack duration) in the same animals that exhibited DOI-induced reductions in defensive behaviors during the WC test (Muehlenkamp et al. 1995).
  22. ↑ Muehlenkamp F, Lucion A, Vogel WH (April 1995). "Effects of selective serotonergic agonists on aggressive behavior in rats". Pharmacology Biochemistry and Behavior. 50 (4): 671–674. doi:10.1016/0091-3057(95)00351-7. PMID   7617717. S2CID   12774131.
  23. ↑ Parrish JC, Braden MR, Gundy E, Nichols DE (December 2005). "Differential phospholipase C activation by phenylalkylamine serotonin 5-HT 2A receptor agonists". Journal of Neurochemistry. 95 (6): 1575–1584. doi: 10.1111/j.1471-4159.2005.03477.x . PMID   16277614. S2CID   24005602.
  24. ↑ "INN Proposed List 55". World Health Organization (WHO). 9 April 1986. Retrieved 2024-11-03.
  25. ↑ "INN Recommended List 26". World Health Organization (WHO). 9 June 1986. Retrieved 2024-11-03.
  26. ↑ Emerson A, Ponté L, Jerome L, Doblin R (2014). "History and future of the Multidisciplinary Association for Psychedelic Studies (MAPS)". J Psychoactive Drugs. 46 (1): 27–36. doi:10.1080/02791072.2014.877321. PMID   24830183.
  27. ↑ World Health Organization (2024). "Use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances, 2024" (PDF). World Health Organization. pp. 152–153. Retrieved 2024-10-21.
  28. ↑ "List of psychotropic substances under international control" (PDF). Archived from the original (PDF) on 2007-03-02. Retrieved 2007-03-30.
  29. ↑ "(15) 4-Bromo-2,5-dimethoxyamphetamine (4-Bromo-2,5-dimethoxy-α-methylbenzeneethanamine)". Isomer Design. Archived from the original on 2021-11-23.
  30. 1 2 Department of Health and Aged Care (October 2015). "Poisons Standard". Federal Register of Legislation. Australian Government.
  31. ↑ "Об утверждении значительного, крупного и особо крупного размеров наркотических средств и психотропных веществ, а также значительного, крупного и особо крупного размеров для растений, содержащих наркотические средства или психотропные вещества, либо их частей, содержащих наркотические средства или психотропные вещества, для целей статей 228, 228.1, 229 и 229.1 Уголовного кодекса Российской Федерации" [On approval of significant, large and especially large sizes of narcotic drugs and psychotropic substances, as well as significant, large and especially large sizes for plants containing narcotic drugs or psychotropic substances, or their parts containing narcotic drugs or psychotropic substances, for the purposes of Articles 228, 228.1, 229 and 229.1 of the Criminal Code of the Russian Federation]. Постановление Правительства РФ от 01.10.2012 N 1002[Resolution of the Government of the Russian Federation of 01.10.2012 N 1002] (in Russian).
  32. ↑ Bartels Jr JR (14 September 1973). "Part 308 – Schedules of Controlled Substances; Additions to Schedule I" (PDF). Federal Register. Vol. 38, no. 183. Drug Enforcement Administration. Archived from the original (PDF) on 2022-03-03. Retrieved 2023-09-30– via Isomer Design.
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