6-APB

Last updated

6-APB
6APB.svg
6-APB molecule ball.png
Clinical data
Other names6-(2-Aminopropyl)benzofuran
Routes of
administration 		By mouth, insufflation
Drug class Serotonin–norepinephrine–dopamine releasing agent; Serotonin 5-HT2 receptor agonist; Entactogen; Stimulant; Psychedelic
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Onset of action 30–60 minutes
Duration of action 7–10 hours
Identifiers
  • 1-(1-benzofuran-6-yl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C11H13NO
Molar mass 175.231 g·mol−1
3D model (JSmol)
  • NC(C)CC1=CC(OC=C2)=C2C=C1
  • InChI=1S/C11H13NO/c1-8(12)6-9-2-3-10-4-5-13-11(10)7-9/h2-5,7-8H,6,12H2,1H3 Yes check.svgY
  • Key:FQDAMYLMQQKPRX-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

6-APB, also known as 6-(2-aminopropyl)benzofuran, is an entactogen of the phenethylamine, amphetamine, and benzofuran families. [1] 6-APB and related drugs are sometimes informally called "Benzofury" in media reports. It is similar in structure to MDA, but differs in that the 3,4-methylenedioxyphenyl ring system has been replaced with a benzofuran ring. 6-APB is also the unsaturated benzofuran derivative of 6-APDB. It may appear as a tan or brown grainy powder.[ citation needed ]

Contents

While the drug never became particularly popular, it briefly entered the rave and underground clubbing scene in the UK before its sale and import were banned. It falls under the category of research chemicals, sometimes called "legal highs” if uncontrolled. Because 6-APB and other substituted benzofurans have not been explicitly outlawed in some countries, they are often technically legal, contributing to its popularity.[ citation needed ]

6-APB was first described in the scientific literature in 2000 [2] [3] [4] [5] and emerged as a novel designer drug in 2010. [3] [4] [6]

Use and effects

6-APB is reported to produce entactogenic, stimulant, and mild psychedelic effects in humans. [3] [7]

Side effects

Acute psychosis has been associated with recreational use of 6-APB in combination with the synthetic cannabinoid JWH-122. [8]

Interactions

Pharmacology

Small clumps of 6-APB powder 6-APB.jpg
Small clumps of 6-APB powder

Pharmacodynamics

6-APB acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA), with EC50 Tooltip half-maximal effective concentration values for monoamine release of 36 nM for serotonin, 14 nM for norepinephrine, and 10 nM for dopamine in rat brain synaptosomes. [2] [6] Simultaneously, 6-APB is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), with affinities (Ki) of 117 nM for the norepinephrine transporter (NET), 150 nM for the dopamine transporter (DAT), and 2,698 nM for the serotonin transporter (SERT) [1] as well as IC50 Tooltip half-maximal effective concentration values for monoamine reuptake inhibition of 930 nM for serotonin, 190 nM for norepinephrine, and 3,300 nM for dopamine. [6]

In addition to actions at the monoamine transporters, 6-APB is a potent high-efficacy partial agonist or full agonist of the serotonin 5-HT2B receptor (Ki = 3.7 nM; EC50 Tooltip half-maximal effective concentration = 140 nM; Emax Tooltip maximal efficacy = 70%). [1] It has higher affinity for this target than any other site. [9] Moreover, unlike MDMA, 6-APB shows 100-fold selectivity for the serotonin 5-HT2B receptor over the serotonin 5-HT2A and 5-HT2C receptors in terms of affinity. [9] [5] It is notably both more potent and more selective as an agonist of the serotonin 5-HT2B receptor than the reference serotonin 5-HT2B receptor agonist, BW-723C86, which is commonly used for research into the serotonin 5-HT2B receptor.[ citation needed ] Although much more potent at the serotonin 5-HT2B receptor, 6-APB is also a partial agonist of the serotonin 5-HT2A receptor (EC50 = 5,900 nM; Emax = 43%) and shows affinity for the serotonin 5-HT2C receptor (Ki = 270 nM) and the serotonin 5-HT1A receptor (Ki = 1,500 nM). [6] It has been reported to act as an agonist of the serotonin 5-HT2C receptor similarly to the serotonin 5-HT2A and 5-HT2B receptors. [3] [10]

Besides the serotonin 5-HT2 receptors, 6-APB has been found to bind with high affinity to the α2C-adrenergic receptor (Ki = 45 nM), although the significance of this action in humans is unknown. [1] 6-APB showed little other affinity at a wide selection of other sites, with some exceptions like the rodent trace amine-associated receptor 1 (TAAR1). [1] [6]

The potent agonism of the serotonin 5-HT2B receptor makes it likely that 6-APB would be cardiotoxic with chronic or long-term use, as seen with other serotonin 5-HT2B receptor agonists such as the withdrawn serotonergic anorectic fenfluramine. [1] [11]

Pharmacokinetics

The pharmacokinetics of 6-APB have not been studied, however, some information can be extracted from user reports. [3] These suggest a slow onset of 40 to 120 minutes. [3] The drugs peak effects last 7 hours, followed by a comedown phase of approximately 2 hours, and after effects for up to 24 hours. [3]

Metabolism

Although limited literature is available, there is some data on metabolism of 6-APB in rats. Its Phase I metabolism involves hydroxylation of the furan ring, then cleavage of the ring, followed by a reduction of the unsaturated aldehyde from the previous step. The resulting aldehyde may then take two paths. It is either oxidized to a carboxylic acid or reduced to an alcohol, and then hydroxylated. Phase II metabolism consists of glucuronidation. The most prevalent metabolites in rats were 3-carboxymethyl-4-hydroxyamphetamine and 4-carboxymethyl-3-hydroxyamphetamine. [12]

Chemistry

6-APB, also known as 6-(2-aminopropyl)benzofuran, is a phenethylamine, amphetamine, and benzofuran and an analogue of 3,4-methylenedioxyamphetamine (MDA).

Synthesis

Synthesis of 6-APB and its structural isomer 4-APB Synthesis of 6-APB and its structural isomer 4-APB.png
Synthesis of 6-APB and its structural isomer 4-APB

The chemical synthesis of 6-APB has been described. [5] The synthesis by Briner and colleagues [5] entailed refluxing 3-bromophenol with bromoacetaldehyde diethylacetal and sodium hydride to give the diethyl acetal, which then was heated with polyphosphoric acid to give a mixture of bromobenzofuran structural isomers: 4-bromo-1-benzofuran and 6-bromo-1-benzofuran. The isomers were separated by silica gel column chromatography, then converted to their respective propanone derivatives, and then reductively aminated to give 6-APB and 4-APB, both of which were converted to their HCl ion pairs for further examination.

Reagent results

6-APB and its structural isomer 5-APB have been tested with a series of agents including: Marquis, Liebermann, Mecke, and Froehde reagents. [14] Exposing compounds to the reagents gives a colour change which is indicative of the compound under test.

Compound Marquis Mecke Mandelin Liebermann Froehde Gallic Ehrlich Hofmann Simon's Folin
6-APBPurplePurple to blackPurple to blackBlackPurpleBrownOrangeLight orangeNo reactionLight orange
6-APB succinatePurplePurple to blackPurple to blackBlackPurpleBrownFaint orangeNo reactionNo reactionLight orange

6-APB succinate is reported to be practically insoluble in CHCl3 as well as very minimally soluble in cold water. A batch seized by the DEA contained a 2:1 ratio of succinate to 6-APB. [13]

Analogues

Analogues of 6-APB include MDA, 6-APDB, 6-MAPB, 5-APB, 6-APBT, and 6-API, among others.

History

6-APB, along with 5-APB, was first described in the scientific literature by Karin Briner and colleagues at Eli Lilly and Company in a patent in 2000. [2] [3] [4] [5] They were specifically studied as serotonin 5-HT2C receptor agonists for potential medical applications at this time. [2] [3] [4] [5] The description of 5-APB and 6-APB in the literature had followed the earlier work on 5-APDB and 6-APDB as serotonin releasing agents and entactogens by David E. Nichols and colleagues at Purdue University in 1993. [4] [6] [15] 6-APB, along with 5-APB, emerged as a novel designer drug in 2010. [3] [4] [6] 5-APB and 6-APB are often confused with 5-APDB and 6-APDB. [4]

Society and culture

Canada

In 1999, amphetamines were changed from Schedule III to Schedule I as a result of the Safe Streets Act. Some have speculated that 6-APB's structure qualifies it as a Schedule I drug as an analog of MDA. [16] [ unreliable source? ]

In 2014, a study funded by the Canadian Institutes of Health Research noted that 6-APB "may or may not be legal in Canada depending on how one interprets the current Act" [17] and that it could be purchased for academic purposes without an exemption from Health Canada. The study also noted how, unlike the MDMA it often serves as a replacement for in countries like the US, 6-APB's benzofuran structure does not make it a direct analogue of amphetamine despite similarities in effects.

China

6-APB has been a controlled substance in China since 1 July 2024 [18]

Finland

6-APB is scheduled in government decree on narcotic substances, preparations and plants and hence is illegal. [19]

France

6-APB is illegal in France. [20]

Germany

6-APB is illegal in Germany since the 17th of July, 2013, when it was added to Anlage II of the Betäubungsmittelgesetz.[ citation needed ]

Italy

6-APB is illegal in Italy. [21]

Luxembourg

In Luxembourg, 6-APB is not cited in the list of prohibited substances. [22] Therefore, it is still a legal substance.

Netherlands

6-APB, as well as multiple substances based on the phenylethamine structure, like most cathinones and amphetamines, are banned under the Opium Law since July 1st, 2025, [23] following an amendment to deal with New Psychoactive Substances (NPS) in the Netherlands. Since this is a structural ban instead of a direct one, later substances that differ slightly but use the same skeleton will also be preemptively banned.

New Zealand and Australia

Certain countries contain a "substantially similar" catch-all clause in their drug law, such as New Zealand and Australia. This includes 6-APB as it is similar in chemical structure to the class A drug MDA, meaning 6-APB may be viewed as a controlled substance analogue in these jurisdictions. [24]

Sweden

In Sweden, as of 27 December 2009 6-APB is classified as "health hazard" under the act Lagen om förbud mot vissa hälsofarliga varor (translated Act on the Prohibition of Certain Goods Dangerous to Health). [25]

It is also classified as a narcotic substance since 2020. [26]

United Kingdom

On June 10, 2013 6-APB and a number of analogues were classified as Temporary Class Drugs in the UK following an ACMD recommendation. [11] This means that sale and import of the named substances are criminal offences and are treated as for class B drugs. [27] On November 28, 2013 the ACMD recommended that 6-APB and related benzofurans should become Class B, Schedule 1 substances. [11] On March 5, 2014 the UK Home Office announced that 6-APB would be made a class B drug on 10 June 2014 alongside every other benzofuran entactogen and many structurally related drugs. [28]

United States

6-APB is not scheduled at the federal level in the United States, [29] [ failed verification ] but it may be considered an analog of amphetamine, in which case purchase, sale, or possession could be prosecuted under the Federal Analog Act. [30]

See also

References

  1. 1 2 3 4 5 6 Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL (January 2013). "Neurochemical profiles of some novel psychoactive substances". European Journal of Pharmacology. 700 (1–3): 147–151. doi:10.1016/j.ejphar.2012.12.006. PMC   3582025 . PMID   23261499.
  2. 1 2 3 4 Brandt SD, Walters HM, Partilla JS, Blough BE, Kavanagh PV, Baumann MH (December 2020). "The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats". Psychopharmacology (Berl). 237 (12): 3703–3714. doi:10.1007/s00213-020-05648-z. PMC   7686291 . PMID   32875347. The synthetic preparation of both 5-APB and 6-APB was first published in 2000 as part of a research program designed for the development of selective 5-HT2C receptor agonists (Briner et al. 2000; Briner et al. 2006), and the preparation of other isomers was reported for forensic purposes a decade later (Casale and Hays 2012; Stanczuk et al. 2013).
  3. 1 2 3 4 5 6 7 8 9 10 Greene SL (2013). "Benzofurans and Benzodifurans". Novel Psychoactive Substances. Elsevier. pp. 383–392. doi:10.1016/b978-0-12-415816-0.00016-x. ISBN   978-0-12-415816-0 . Retrieved 15 April 2025. A patent granted to Eli Lilly and Company in 2006 classifies 5-APB and 6-APB as 5HT2C receptor agonists [15]. [...] Internet user reports of 5-APB and 6-APB date from late 2010 [13]. [...] [15] Briner K, Burkhart JP, Burkholder TM, et al. Aminoalkylbenzofurans as serotonin (5-HT(2c)) agonists. 7045545 (US patent). Published 2000-01-19, issued 2006-16-03.
  4. 1 2 3 4 5 6 7 Roque Bravo R, Carmo H, Carvalho F, Bastos ML, Dias da Silva D (August 2019). "Benzo fury: A new trend in the drug misuse scene". J Appl Toxicol. 39 (8): 1083–1095. doi:10.1002/jat.3774. PMID   30723925. The first benzofurans appearing on the drug scene in 2010‐11, were 5‐(2‐aminopropyl) benzofuran (5‐APB) and 6‐(2‐aminopropyl) benzofuran (6‐APB). These compounds had been previously patented in 2006 as potential therapeutic drugs for eating disorders and seizures, due to their action as serotonergic agonists (Advisory Council on the Misuse of Drugs, 2013; Taschwer, Hofer, & Schmid, 2014). While these first two molecules are the subject of most published investigations, namely those concerning pharmacological aspects, other benzofuran analogues have also been marketed as "legal highs." Examples of such analogues are 5‐(2‐ aminopropyl)‐2,3‐dihydrobenzofuran (5‐APDB) and 6‐(2‐aminopropyl)‐ 2,3‐dihydrobenzofuran (6‐APDB), first synthesized in 1993, purportedly as non‐neurotoxic benzofuran analogues of 3,4‐methylenedioxyamphetamine (MDA) (Monte, Marona‐Lewicka, Cozzi, & Nichols, 1993). These drugs are often confused with 5‐APB and 6‐APB (Casale, 2012; Casale & Hays, 2011).
  5. 1 2 3 4 5 6 USpatent 7045545,Briner K, Burkhart JP, Burkholder TP, Fisher MJ, Gritton WH, Kohlman DT, Liang SX, Miller SC, Mullaney JT, Xu YC, Xu Y,"Aminoalkylbenzofurans as serotonin (5-HT(2c)) agonists",published 19 January 2000,issued 16 May 2006, assigned to Eli Lilly Co.
  6. 1 2 3 4 5 6 7 Rickli A, Kopf S, Hoener MC, Liechti ME (July 2015). "Pharmacological profile of novel psychoactive benzofurans". British Journal of Pharmacology. 172 (13): 3412–3425. doi:10.1111/bph.13128. PMC   4500375 . PMID   25765500. [5-APB] and [6-APB] are benzofuran analogues of MDA (Figure 1). [5-APDB] and [6-APDB] are dihydrobenzofuran analogues (Figure 1) that were originally synthesized for research purposes (Monte et al., 1993). [...] 5-APB and 6-APB appeared on the drug market in 2010– 2011 (Chan et al., 2013; Jebadurai et al., 2013; Stanczuk et al., 2013; Archer et al., 2014; Elliott and Evans, 2014; King, 2014), with reports of intoxication (Chan et al., 2013; Greene, 2013; Jebadurai et al., 2013; Seetohul and Pounder, 2013).
  7. ↑ Canal CE (2018). "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action". New Psychoactive Substances. Handbook of Experimental Pharmacology. Vol. 252. Cham: Springer International Publishing. pp. 227–260. doi: 10.1007/164_2018_107 . ISBN   978-3-030-10560-0. PMC   6136989 . PMID   29532180. Despite micromolar 5-HT1A affinities (Rickli et al. 2015b), Nbenzylphenethylamines retain potent psychedelic effects. Also, benzofurans, such as 5-APB and 6-APB, are potent and efficacious 5-HT2B agonists but have very low potency at 5-HT2A receptors. They also stimulate efflux of DA and 5-HT and have activity at TAAR1 receptors (Iversen et al. 2013; Rickli et al. 2015a), but anecdotal reports note that psychedelic effects are relatively minor compared to classic psychedelics. These observations provide further credence that the 5-HT2A receptor, but not 5-HT1A, 5-HT2B, TAAR1, or monoamine transporters, initiates psychedelic effects.
  8. ↑ Chan WL, Wood DM, Hudson S, Dargan PI (September 2013). "Acute psychosis associated with recreational use of benzofuran 6-(2-aminopropyl)benzofuran (6-APB) and cannabis". Journal of Medical Toxicology. 9 (3): 278–81. doi:10.1007/s13181-013-0306-y. PMC   3770991 . PMID   23733714.
  9. 1 2 Canal CE, Murnane KS (January 2017). "2C receptor and the non-addictive nature of classic hallucinogens". Journal of Psychopharmacology. 31 (1): 127–143. doi:10.1177/0269881116677104. PMC   5445387 . PMID   27903793.
  10. ↑ USpatent 7045545,Karin Briner et al,"Aminoalkylbenzofurans as serotonin (5-HT(2c)) agonists",published 2000-01-19,issued 2006-16-03
  11. 1 2 3 Browne J (4 June 2013). "Temporary class drug order on benzofury and NBOMe compounds - letter from ACMD". Advisory Council on the Misuse of Drugs. GOV.UK.
  12. ↑ Nugteren-van Lonkhuyzen JJ, van Riel AJ, Brunt TM, Hondebrink L (December 2015). "Pharmacokinetics, pharmacodynamics and toxicology of new psychoactive substances (NPS): 2C-B, 4-fluoroamphetamine and benzofurans". Drug and Alcohol Dependence. 157: 18–27. doi:10.1016/j.drugalcdep.2015.10.011. PMID   26530501.
  13. 1 2 Casale JF, Hays PA (January 2012). "The Characterization of 6-(2-Aminopropyl)benzofuran and Differentiation from its 4-, 5-, and 7-Positional Analogues" (PDF). Microgram Journal. 9 (2): 61–74. Archived from the original (PDF) on 2016-11-05. Retrieved 2016-06-08.
  14. ↑ "Results". PRO Test. Retrieved 2021-06-01.
  15. ↑ Luethi D, Liechti ME (April 2020). "Designer drugs: mechanism of action and adverse effects". Arch Toxicol. 94 (4): 1085–1133. doi:10.1007/s00204-020-02693-7. PMC   7225206 . PMID   32249347. Some benzofuran designer drugs were originally investigated as part of a study that examined the role of ring oxygen atoms in interactions between MDA and monoamine transporters (Monte et al. 1993). [...] Monte AP, Marona-Lewicka D, Cozzi NV, Nichols DE (1993) Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine. J Med Chem 36(23):3700–3706. https://doi.org/10. 1021/jm00075a027{{cite journal}}: External link in |quote= (help)
  16. ↑ "Controlled Drugs and Substances Act : Definitions and Interpretations". isomerdesign.com. Retrieved 2019-11-11.
  17. ↑ Hudson AL, Lalies MD, Baker GB, Wells K, Aitchison KJ (2014-04-16). "Ecstasy, legal highs and designer drug use: A Canadian perspective". Drug Science, Policy and Law . 1 2050324513509190. doi: 10.1177/2050324513509190 . ISSN   2050-3245. S2CID   159675835.
  18. ↑ National Medical Products Administration (NMPA) of China (July 22, 2024). "关于将溴啡等46种物质列入《非药用类麻醉药品和精神药品管制品种增补目录》的公告".
  19. ↑ "Ajantasa". finlex.fi.
  20. ↑ "Arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants".
  21. ↑ "Nuove tabelle delle sostanze stupefacenti e psicotrope (DPR 309/90)" (PDF) (in Italian). Ministero della Salute. Archived from the original (PDF) on 2016-02-06. Retrieved 2016-05-31.
  22. ↑ "Loi du 19 février 1973 concernant la vente de substances médicamenteuses et la lutte contre la toxicomanie. - Legilux". legilux.public.lu. Retrieved 2021-06-01.
  23. ↑ "Lijst verboden Nieuwe Psychoactieve Stoffen (NPS) per 1 juli 2025". www.rijksoverheid.nl. July 2025. Retrieved 2025-07-10.
  24. ↑ "Misuse of Drugs Act 1975". New Zealand Legislation. 7 November 2015.
  25. ↑ "Förordning (1999:58) om förbud mot vissa hälsofarliga varor" (in Swedish). Lagbevakning med Notisum och Rättsnätet. 24 November 2009. Archived from the original on 4 October 2013. Retrieved 15 September 2013.
  26. ↑ "Förordning (1992:1554) om kontroll av narkotika". www.riksdagen.se (in Swedish). Retrieved 2025-07-14.
  27. ↑ Browne J (4 June 2013). "'NBOMe' and 'Benzofury' banned". Home Office. GOV.UK.
  28. ↑ UK Home Office (28 April 2014). "The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014". The National Archives.
  29. ↑ "21 CFR — SCHEDULES OF CONTROLLED SUBSTANCES §1308.11 Schedule I." Archived from the original on 2009-08-27. Retrieved 2018-04-10.
  30. ↑ Casale JF, Hays PA (January 2011). "The characterization of 5-and 6-(2-aminopropyl)-2, 3-dihydrobenzofuran". Microgram J. 8 (2): 62–74.
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