:AH-7921
{{Short description|Opioid analgesic}}
{{cs1 config|name-list-style=vanc}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477235538
| IUPAC_name = 3,4-dichloro-N-
| image = AH-7921 structure.svg
| width = 220
| image2 = AH-7921 3D BS.png
| width2 = 220
| tradename =
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU = S9
| legal_BR = F1
| legal_CA = Schedule I
| legal_UK = Class A
| legal_US = Schedule I
| legal_DE = Anlage II
In General Unscheduled, Illegal in Sweden, Czech Republic, China, Brazil and Israel.
| routes_of_administration = Recreational: insufflation, sublingual, intravenous, oral, rectal
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|changed|cas}}
| CAS_number = 55154-30-8
| ATC_prefix = none
| ATC_suffix =
| PubChem = 187760
| KEGG = C22729
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 163208
| synonyms = AH-7921
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 10BR7A0SO0
| C=16 | H=22 | Cl=2 | N=2 | O=1
| smiles = ClC1=CC=C(C(NCC2(CCCCC2)N(C)C)=O)C=C1Cl
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H22Cl2N2O/c1-20(2)16(8-4-3-5-9-16)11-19-15(21)12-6-7-13(17)14(18)10-12/h6-7,10H,3-5,8-9,11H2,1-2H3,(H,19,21)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JMZROFPPEXCTST-UHFFFAOYSA-N
}}
AH-7921 (Doxylam) is an opioid analgesic drug selective for the μ-opioid receptor, having around 90% the potency of morphine when administered orally.{{cite journal | vauthors = Brittain RT, Kellett DN, Neat ML, Stables R | title = Proceedings: Anti-nociceptive effects in N-substituted cyclohexylmethylbenzamides | journal = British Journal of Pharmacology | volume = 49 | issue = 1 | pages = 158P–159P | date = September 1973 | pmid = 4207044 | pmc = 1776456 | doi = 10.1111/j.1476-5381.1973.tb08279.x }}{{cite journal | vauthors = Hayes AG, Tyers MB | title = Determination of receptors that mediate opiate side effects in the mouse | journal = British Journal of Pharmacology | volume = 79 | issue = 3 | pages = 731–736 | date = July 1983 | pmid = 6317119 | pmc = 2044905 | doi = 10.1111/j.1476-5381.1983.tb10011.x }}{{cite journal | vauthors = Harper NJ, Veitch GB, Wibberley DG | title = 1-(3,4-Dichlorobenzamidomethyl)cyclohexyldimethylamine and related compounds as potential analgesics | journal = Journal of Medicinal Chemistry | volume = 17 | issue = 11 | pages = 1188–1193 | date = November 1974 | pmid = 4416926 | doi = 10.1021/jm00257a012 }} It was discovered in the 1970s{{ cite patent | country = US | number = 3975443 | status = patent | inventor = Harper N, Veitch G | title = 1-(3,4-Dichlorobenzamidomethyl)-cyclohexyldimethylamine | gdate = 1976-08-17 | assign1 = Allen & Hanburys }} by a team at Allen and Hanburys located in the United Kingdom.{{cite web|url=http://www.deadiversion.usdoj.gov/fed_regs/rules/2016/fr0414_4.htm|title=2016 - Final Order: Placement of AH-7921 Into Schedule I|website=www.deadiversion.usdoj.gov|language=en-US|access-date=2017-12-03}} The drug is considered a new psychoactive substance (NPS) in which it is synthetically created in laboratories to mimic that of controlled substances. The substance has also been sold on the internet since 2012 as a "research chemical".{{cite journal | vauthors = Katselou M, Papoutsis I, Nikolaou P, Spiliopoulou C, Athanaselis S | title = AH-7921: the list of new psychoactive opioids is expanded | journal = Forensic Toxicology | volume = 33 | issue = 2 | pages = 195–201 | date = 2015 | pmid = 26257832 | pmc = 4525185 | doi = 10.1007/s11419-015-0271-z }} When sold online it may be called the alternative name doxylam, not to be confused with doxylamine.{{cite journal | vauthors = Zawilska JB | title = An Expanding World of Novel Psychoactive Substances: Opioids | journal = Frontiers in Psychiatry | volume = 8 | pages = 110 | date = 2017-06-30 | pmid = 28713291 | pmc = 5492455 | doi = 10.3389/fpsyt.2017.00110 | doi-access = free }} AH-7921 has never progressed to clinical trials.{{cite news | date = 10 January 2017 | veditors = Krasowski MD, Brown J | url= http://online.csp.edu/blog/forensic-scholars-today/designer-drugs |title=The New Wave of Designer Drugs | work = Forensic Scholars Today | publisher = Concordia University, St. Paul Online|access-date=2017-12-03|language=en-US}} The DEA is not aware of any medical usage in the United States, and has not insisted the Health and Human Services department (HHS) to conduct any medical research of the substance's uses.
Side effects and withdrawal
With doses that usually range from 10 to 150 mg, users are likely to experience effects similar to heroin, morphine, and fentanyl such as euphoria and respiratory depression. When an overdose occurs users often experience tachycardia, hypertension, and seizures. Mice, dogs, and monkeys, have been used in tests which showed the drug was almost equivalently potent to morphine, and had a very steep dose response curve.{{cite journal | vauthors = Wohlfarth A, Scheidweiler KB, Pang S, Zhu M, Castaneto M, Kronstrand R, Huestis MA | title = Metabolic characterization of AH-7921, a synthetic opioid designer drug: in vitro metabolic stability assessment and metabolite identification, evaluation of in silico prediction, and in vivo confirmation | journal = Drug Testing and Analysis | volume = 8 | issue = 8 | pages = 779–791 | date = August 2016 | pmid = 26331297 | pmc = 4562414 | doi = 10.1002/dta.1856 }} Rats given 20 mg doses three times a day for five days, experienced withdrawal symptoms similar to other opioids. Reports have shown users to experience depression and insomnia when withdrawing from this drug.
Chemistry
AH-7921 is commonly found as an off-white solid with a melting point between 215–216º Celsius. It is one single covalently bonded unit with 4 rotatable bonds. It also has two hydrogen bond acceptors, and one hydrogen bond donor.{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/187760#section=chemical-and-physical-properties|title=
Use
Although AH-7921 was extensively studied in vitro and in animals, though not in humans, by the developing company, it was never sold commercially for medical use. In 2013, AH-7921 was discovered to have been used as an active ingredient in "synthetic cannabis" products in Japan.{{cite journal | title=Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products | vauthors = Uchiyama N, Matsuda S, Kawamura M, Kikura-Hanajiri R, Goda Y | journal=Forensic Toxicology |date=July 2013 | volume=31 | issue=2 | pages=223–240 | doi=10.1007/s11419-013-0182-9|s2cid=1279637 }}
In October 2015, two horses (Bossmon and Literata) trained by owner-trainer Roy Sedlacek tested positive for AH-7921 at Belmont Park racetrack.{{cite web | vauthors = Godfrey N | date = 12 November 2015 |title=Two horses test positive for designer drug |work=Racing Post |url=http://www.racingpost.com/news/horse-racing/usa-two-horses-test-positive-for-designer-drug/1987810/|archive-url=https://web.archive.org/web/20151117015014/http://www.racingpost.com/news/horse-racing/usa-two-horses-test-positive-for-designer-drug/1987810/|url-status=dead|archive-date=17 November 2015|access-date=29 April 2016}} Norway and Iceland use this substance as an analytical reference standard in which it can be ordered online from chemical suppliers; however, labels are required to state that it is not for human consumption thus conforming to the law. Within ten months from 2013 to 2014, there had been serious fatalities reported from this drug from four different countries. The first fatality was a 19-year-old male who had a 3.9 mg/L AH-7921 concentration of heart blood leading medical examiners to confirm the death was an opioid intoxication.{{cite journal | vauthors = Vorce SP, Knittel JL, Holler JM, Magluilo J, Levine B, Berran P, Bosy TZ | title = A fatality involving AH-7921 | journal = Journal of Analytical Toxicology | volume = 38 | issue = 4 | pages = 226–230 | date = May 2014 | pmid = 24523294 | doi = 10.1093/jat/bku011 | doi-access = }} In another case, a 22-year-old woman was found dead with a femoral blood to AH-7921 concentration of 450 μg/L.{{cite journal | vauthors = Fels H, Krueger J, Sachs H, Musshoff F, Graw M, Roider G, Stoever A | title = Two fatalities associated with synthetic opioids: AH-7921 and MT-45 | journal = Forensic Science International | volume = 277 | pages = e30–e35 | date = August 2017 | pmid = 28506719 | doi = 10.1016/j.forsciint.2017.04.003 }}
A 2018 review of published case reports found a total of 14 cases, of which 13 resulted in death.{{cite journal | vauthors = Rambaran KA, Amin ZM, Fleming SW, Chacko L, Alzghari SK | title = AH-7921: A review of previously published reports | journal = Proceedings | volume = 31 | issue = 3 | pages = 303–306 | date = July 2018 | pmid = 29904293 | pmc = 5997081 | doi = 10.1080/08998280.2018.1465320 }} The oral route of administration was reported in two cases, and most cases reported use of concomitant pharmaceutical agents. Postmortem autopsies found that pulmonary edema was the most common finding, with nine of the cases having heavier lungs. Overall, fatalities occurred with low and high concentrations of AH-7921 in femoral blood.
Legality
AH-7921 was made a Prohibited Substance (Schedule 9 of the Standard for the Uniform Scheduling of Medicines and Poisons) in Australia in May 2014.{{cite web | url = https://www.tga.gov.au/sites/default/files/scheduling-decisions-1405-final.pdf | title = Final decisions and reasons for decisions by delegates of the Secretary to the Department of Health | date = May 2014 | work = Therapeutic Goods Administration (TGA) | publisher = Commonwealth of Australia }} Although this amendment was repealed in June 2014,{{cite web | url = https://www.legislation.gov.au/Details/F2014L00566 | title = Poisons Standard Amendment No. 2 of 2014 | work = Federal Register of Legislation | date = 19 May 2014 | publisher = Commonwealth of Australia }} which simply means the amendment document ceases, but the actual scheduling is permanent as part of the main document (all SUSMP amendments cease after a few weeks). It may, however, still be a banned import.
AH-7921 has been illegal to distribute in Israel since December 2013.{{cite web | url = http://www.nevo.co.il/Law_word/law01/P170_001.doc | title = פקודת הסמים המסוכנים נוסח חדש, תשל"ג -1973 | trans-title = The Dangerous Drugs Ordinance, new version, 5733 | language = Hebrew }}
In the UK, AH-7921 was included as a Class A drug in January 2015 as part of The Misuse of Drugs Act 1971 (Amendment) (No. 2) Order 2014.{{cite web | url = http://www.legislation.gov.uk/uksi/2014/3271/made | title = The Misuse of Drugs Act 1971 (Amendment) (No. 2) Order 2014 | work = Legislation.gov.uk }}
In Brazil, AH-7921 has been an illegal drug since May 2015.{{cite web | url = http://portal.anvisa.gov.br/documents/10181/2879690/(1)RDC_87_2016.pdf/ | title = Resolução da Diretoria Colegiada - RDC nº 87 de 28/06/2016 | trans-title = Resolution of the Board of Directors - RDC nº 87 of 28/06/2016 | language = Portuguese }}
As of October 2015 AH-7921 is a controlled substance in China.{{cite web | url=http://www.sfda.gov.cn/WS01/CL0056/130753.html | title=关于印发《非药用类麻醉药品和精神药品列管办法》的通知 | trans-title = Notice on Printing and Distributing the "Measures for the Scheduling of Non-Pharmaceutical Narcotic Drugs and Psychotropic Substances" | publisher=China Food and Drug Administration | date=27 September 2015 | language=Chinese | access-date=1 October 2015 | archive-url=https://web.archive.org/web/20151001222554/http://www.sfda.gov.cn/WS01/CL0056/130753.html | archive-date=1 October 2015 | url-status=dead }}
In the United States, AH-7921 was placed into Schedule I of the Controlled Substances Act on May 16, 2016, due to its lack of medical use.{{cite web | url=http://www.deadiversion.usdoj.gov/fed_regs/rules/2016/fr0414_4.htm | title=Schedules of Controlled Substances: Placement of AH-7921 Into Schedule I | work = Drug Enforcement Administration | publisher = U.S. Department of Justic | date=14 April 2016}} Furthermore, any person who wishes to manufacture, distribute, import, export, research, and educate using the substance, must be registered by the Drug Enforcement Administration.
The Canadian Controlled Drugs and Substances Act was amended in 2016 to include the substance as a Schedule I substance. Possession without legal authority can result in maximum 7 years imprisonment. Further, Health Canada amended the Food and Drug Regulations in May, 2016 to classify AH-7921 as a restricted drug.{{cite web | url = http://www.gazette.gc.ca/rp-pr/p2/2016/2016-06-01/html/sor-dors106-eng.php | title = Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18) | date = June 2016 | publisher = The Government of Canada }} Only those with a law enforcement agency, person with an exemption permit or institutions with Minister's authorization may possess the drug in Canada.