6-APB

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6-APB
Benzofuran2DACSL.svg
Ball-and-stick model of the 6-APB molecule
Systematic (IUPAC) name
6-(2-aminopropyl)benzofuran
Legal status
Legal status
Identifiers
CAS Number 286834-85-3 N 286834-84-2 (HCl)
ATC code none
PubChem CID 9794343
ChemSpider 7970110 YesY
UNII 285VE60914
Chemical data
Formula C11H13NO
Molar mass 175.23 g/mol
 NYesY (what is this?)  (verify)

6-(2-aminopropyl)benzofuran or 1-benzofuran-6-ylpropan-2-amine (6-APB), also known as Benzofury, is an entactogenic compound of the phenethylamine and amphetamine classes. It is a recreational drug that 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. 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." Because they have not been explicitly outlawed in some countries, they are often technically legal, contributing to their popularity. It was first synthesized by David Nichols and his team in 1993 while studying non-neurotoxic analogs of MDMA. 6-APB is often confused with the very similar 6-APDB which is lacking a double bond on carbon 2 and 3 of the furan ring. It may appear as a tan grainy powder.

Pharmacology[edit]

Pharmacodynamics[edit]

6-APB is a triple monoamine reuptake inhibitor with Ki values of 117, 150 and 2698 nM for NET, DAT and SERT respectively as well as being a potent agonist for the 5-HT2B receptor (Ki 3.7 nM).[1] The subjective effects and structure–activity relationship suggest that it is also a releasing agent.

The agonism for 5-HT2B makes it likely that 6-APB would be cardiotoxic with long term use, as seen in other 5-HT2B agonists, such as fenfluramine and MDMA.[1][2] 6-APB acts as an agonist of the 5-HT2C receptor,[3] which may be responsible for its appetite suppression. While 6-APB is an agonist at all three 5-HT2 receptor subtypes, its affinity for 5-HT2B is significantly higher. It is both more potent and more selective over other serotonin receptors than the reference agonist, BW723C86, which is commonly used for research into 5-HT2B receptors.

Pharmacokinetics[edit]

The pharmacokinetics of 6-APB have not been studied, however, some information can be extracted from user reports. These suggest an slow onset of 20–120 minutes. The drugs maximum effects last 3–4 hours, followed by a comedown phase of up to 24 hours.[4]

Metabolism[edit]

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 takes 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-hydroxy-amphetamine and 4-carboxymethyl-3-hydroxy-amphetamine.[5]

The agonism for 5-HT2B makes it likely that 6-APB would be cardiotoxic with long term use, as seen in other 5-HT2B agonists, such as fenfluramine and MDMA.[1][2] 6-APB acts as an agonist of the 5-HT2C receptor,[3] which may be responsible for its appetite suppression. While 6-APB is an agonist at all three 5-HT2 receptor subtypes, its affinity for 5-HT2B is significantly higher. It is both more potent and more selective over other serotonin receptors than the reference agonist, BW723C86, which is commonly used for research into 5-HT2B receptors.

Reactions[edit]

6-APB and it's structural isomer 5-APB have been tested with a series of agents including: Marquis, Liebermann, Mecke, and Froehde reagents. Reagent testing is performed by obtaining a small amount of the substance in question and dripping the selected reagent onto it. Each reagent tests for a chemical property and will change to a specific color in an allotted time to analyze the results. Marquis reagent is composed of a mixture of sulfuric acid and formaldehyde and detects certain alkaloids and will go from colored purple to black in 0–5 seconds when added to a variety of substances, most notable MDMA and MDA. Marquis reagent and 6-APB also has reported some fizzing but no smoke. Lieberman reagent is a mixture of potassium nitrite and concentrated sulfuric acid and also identifies alkaloids as well as other substances from its test. 6-APB turned dark purple when in contact with Liebermann reagent which, unlike the Marquis reagent, is not unique to either MDA or MDMA. Mecke reagent is composed of a mixture of selenous acid and concentrated sulfuric acid and turns purple when in contact with 6-APB. And Froehde reagent can be a combination of molybdic acid or a molybdate salt dissolved in hot, concentrated sulfuric acid, which, when added to 6-APB, turns purple as well.[6]

Compound Marquis Liebermann Mecke Froehde
5-APB Black Black Black Dark Purple
6-APB Purple Dark Purple Purple Purple

As for solubility, 6-APB is reported to be practically insoluble in CHCl3 as well as very minimally soluble in cold H2O.[7]

Synthesis[edit]

Exact experimental details are not provided, but roughly follow the provided procedure. The procedure of Briner et al.[3] was the most comprehensive thus far and was replicated by Casale and Hays[7] as described below.

Briefly, bromophenol was refluxed with bromoacetaldehyde and NaH to give the diethyl acetyl, which then was heated with polyphosphoric acid to give a mixture of bromobenzofurans structural isomers: 4-Bromo-1-benzofuran and 6-Bromo-1-benzofuran. Both isomers were separated via silica gel column chromatography, then catalytically converted to their respective 2-propanones, and then reductively aminated to 6-APB and 4-APB. Both of which were converted to their HCl ion-pairs for further examination.

Synthesis of 6-APB and its structural isomer 4-APB drawn on JSDraw 4 following the reaction scheme from: http://forendex.southernforensic.org/uploads/references/MicrogramJournal/9.2.61.74.pdf

Effects[edit]

Users report a feeling a sense of euphoria and energy. The effect has been most closely compared with those of ecstasy.[8] Adverse effects include loss of appetite, hallucinations, severe paranoia, tachycardia, insomnia, and jaw tensions. Users warn of neurotoxicity and brain damage, although the reports are unconfirmed. Web forum users also report serotonin syndrome, especially if combined with SSRI's. These side effects are similar to MDA, but much more profound than MDMA. Researchers claim that it produces about the same addiction as amphetamines.[8]

Law[edit]

Canada[edit]

6-APB is Schedule III[9] in Canada as it is an analogue of MDA.[10] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1.[11]

France[edit]

6-APB is unscheduled in France.

Italy[edit]

6-APB is illegal in Italy.[12]

Germany[edit]

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

Netherlands[edit]

6-APB is not listed under the Opium Law or the Medicine Act in the Netherlands, and thus currently legal.

New Zealand and Australia[edit]

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.[13]

Sweden[edit]

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).[14]

UK[edit]

On June 10, 2013 6-APB and a number of analogues were classified as Temporary Class Drugs in the UK following an ACMD recommendation.[2] This means that sale and import of the named substances are criminal offences and are treated as for class B drugs.[15] On November 28, 2013 the ACMD recommended that 6-APB and related benzofurans should become Class B, Schedule 1 substances.[2] 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.[16]

USA[edit]

6-APB is unscheduled in the United States, but not currently approved by the Food and Drug Administration for human consumption.

See also[edit]

References[edit]

  1. ^ a b c Iversen, L.; Gibbons, S.; Treble, R.; Setola, V.; Huang, X. P.; Roth, B. L. (January 2013). "Neurochemical profiles of some novel psychoactive substances". European Journal of Pharmacology 700 (1–3). doi:10.1016/j.ejphar.2012.12.006. PMC 3582025. PMID 23261499. 
  2. ^ a b c d Advisory Council on the Misuse of Drugs, Jeremy Browne (4 June 2013). "Temporary class drug order on benzofury and NBOMe compounds - letter from ACMD". GOV.UK. 
  3. ^ a b c US patent 7045545, Karin Briner, Joseph Paul Burkhart, Timothy Paul Burkholder, Matthew Joseph Fisher, William Harlan Gritton, Daniel Timothy Kohlman, Sidney Xi Liang, Shawn Christopher Miller, Jeffrey Thomas Mullaney, Yao-Chang Xu, Yanping Xu, "Aminoalkylbenzofurans as serotonin (5-HT(2c)) agonists", published 19 January 2000, issued 16 May 2006 
  4. ^ Shaun L. Greene (2013). Novel Psychoactive Substances: Classification, Pharmacology and Toxicology Chapter 16 – Benzofurans and Benzodifurans. Boston: Academic Press. pp. 383–392. doi:10.1016/B978-0-12-415816-0.00016-X. ISBN 9780124158160. 
  5. ^ Johanna J. Nugteren-van Lonkhuyzen; Antoinette J.H.P. van Riel; Tibor M. Brunt; Laura Hondebrink (December 2015). "Pharmacokinetics, pharmacodynamics and toxicology of new psychoactive substances (NPS): 2C-B, 4-fluoroamphetamine and benzofurans". Drug & Alcohol Dependence 157: 18–27. doi:10.1016/j.drugalcdep.2015.10.011. PMID 26530501. 
  6. ^ Jeremiah Morris. Color Tests and Analytical Difficulties with Emerging Drugs (PDF). Johnson County Sheriff’s Office Criminalistics Laboratory: NIST. p. 36. 
  7. ^ a b John F. Casale, Patrick A. Hays (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. 
  8. ^ a b "Legal Benzo Fury 'as dangerous as illegal drugs such as ecstasy', study claims". Dailymail. 
  9. ^ "Controlled Drugs and Substances Act: Legislative History · Schedule I". Isomer Design. 
  10. ^ "Controlled Drugs and Substances Act: Definitions and Interpretations". Isomer Design. 
  11. ^ "Safe Streets and Communities Act". Justice Laws Website. 2012. 
  12. ^ "Nuove tabelle delle sostanze stupefacenti e psicotrope (DPR 309/90)" (PDF) (in Italian). Ministero della Salute. 
  13. ^ "Misuse of Drugs Act 1975". New Zealand Legislation. 7 November 2015. 
  14. ^ "Förordning (1999:58) om förbud mot vissa hälsofarliga varor" (in Swedish). Lagbevakning med Notisum och Rättsnätet. 24 November 2009. 
  15. ^ Home Office, Jeremy Browne (4 June 2013). "'NBOMe' and 'Benzofury' banned". GOV.UK. 
  16. ^ UK Home Office (28 April 2014). "The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014". The National Archives.