Diphenidine Explained

Iupac Name:(±)-1-(1,2-Diphenylethyl)piperidine
Legal Br:F2
Legal Br Comment:[1]
Legal Ca:Schedule I
Legal De:Anlage II
Legal Uk:PSA
Legal Un:P II
Cas Number:36794-52-2
Pubchem:206666
Kegg:C22733
Chebi:104234
Chembl:4303426
Chemspiderid:179031
Unii:H8Q4VPL82Y
C:19
H:23
N:1
Melting Point:210
Smiles:c1ccc(cc1)CC(c2ccccc2)N3CCCCC3
Stdinchi:1S/C19H23N/c1-4-10-17(11-5-1)16-19(18-12-6-2-7-13-18)20-14-8-3-9-15-20/h1-2,4-7,10-13,19H,3,8-9,14-16H2
Stdinchikey:JQWJJJYHVHNXJH-UHFFFAOYSA-N

Diphenidine (1,2-DEP, DPD, DND) is a dissociative anesthetic that has been sold as a designer drug.[2] [3] [4] The synthesis of diphenidine was first reported in 1924, and employed a Bruylants reaction analogous to the one that would later be used to discover phencyclidine in 1956.[2] Shortly after the 2013 UK ban on arylcyclohexylamines, diphenidine and the related compound methoxphenidine became available on the grey market.[2] Anecdotal reports describe high doses of diphenidine producing "bizarre somatosensory phenomena and transient anterograde amnesia."[2] Diphenidine and related diarylethylamines have been studied in vitro as treatments for neurotoxic injury and are antagonists of the NMDA receptor.[5] [6] [7] [8] In dogs diphenidine exhibits greater antitussive potency than codeine phosphate.[9] [10]

Electrophysiological analysis demonstrates that the amplitude of NMDA-mediated fEPSPs are reduced by diphenidine and ketamine to a similar extent, with diphenidine displaying a slower onset of antagonism.[11] The two enantiomers of diphenidine differ greatly in their ability to block the NMDA receptor, with the more potent (S)-enantiomer possessing affinity forty times higher than the (R)-enantiomer.[6] Since diphenidine's introduction in 2013 vendors have stated the drug "acts on dopamine transport" yet no data concerning the action of diphenidine on the dopamine transporter was published until 2016.[2] Diphenidine's highest affinity is for the NMDA receptor, but it does display submicromolar affinity for the σ1 receptor, σ2 receptor and dopamine transporter.[12] [13]

Since 2014 there have been several published reports of diphenidine being sold in combination with other research chemicals, particularly synthetic cannabinoids and stimulants in Japanese herbal incense blends.[14] [15] [16] The first reported seizure concerned a Japanese product called "fragrance powder" containing diphenidine and benzylpiperazine.[17] A herbal incense sold in the Shizuoka Prefecture under the name "Aladdin Edition" was found to contain diphenidine and 5F-AB-PINACA at concentrations of 289 mg/g and 55.5 mg/g, respectively.[14] A product called Herbal Incense. The Super Lemon containing AB-CHMINACA, 5F-AMB, and diphenidine was implicated in a fatal poisoning.[15] Most recently diphenidine consumed in conjunction with three substituted cathinones, three benzodiazepines, and alcohol was implicated in a fatal ingestion of "bath salt" and "liquid aroma" products in Japan.[18]

In Canada, MT-45 and its analogues were made Schedule I controlled substances, which includes DPD in its structural group.[19] Possession without legal authority can result in maximum seven years imprisonment. Further, Health Canada amended the Food and Drug Regulations in May, 2016 to classify explicitly DPD as a restricted drug. Only those with a law enforcement agency, person with an exemption permit or institutions with Minister's authorization may possess the drug.

See also

Notes and References

  1. Web site: Anvisa . Brazilian Health Regulatory Agency . 2023-07-24 . 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. live . https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 . 2023-08-27 . 2023-08-27 . . pt-BR . 2023-07-25.
  2. Morris H, Wallach J . From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs . Drug Testing and Analysis . 6 . 7–8 . 614–632 . July–August 2014 . 24678061 . 10.1002/dta.1620 .
  3. Wink CS, Michely JA, Jacobsen-Bauer A, Zapp J, Maurer HH . Diphenidine, a new psychoactive substance: metabolic fate elucidated with rat urine and human liver preparations and detectability in urine using GC-MS, LC-MSn, and LC-HR-MSn . Drug Testing and Analysis . 8 . 10 . 1005–1014 . October 2016 . 26811026 . 10.1002/dta.1946 .
  4. Helander A, Beck O, Bäckberg M . Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine . Clinical Toxicology . 53 . 5 . 446–453 . June 2015 . 25881797 . 10.3109/15563650.2015.1033630 . 5962038 .
  5. 1,2-diarylethylamines for treatment of neurotoxic injury . EP . 0346791 . G.D. Searle, LLC . Gray NM, Cheng BK . 6 April 1994 .
  6. Berger ML, Schweifer A, Rebernik P, Hammerschmidt F . NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds . Bioorganic & Medicinal Chemistry . 17 . 9 . 3456–3462 . May 2009 . 19345586 . 10.1016/j.bmc.2009.03.025 .
  7. Espinosa L, Itzstein C, Cheynel H, Delmas PD, Chenu C . Active NMDA glutamate receptors are expressed by mammalian osteoclasts . The Journal of Physiology . 518 . Pt 1 . 47–53 . July 1999 . 10373688 . 2269403 . 10.1111/j.1469-7793.1999.0047r.x .
  8. Rogawski MA . Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines . Trends in Pharmacological Sciences . 14 . 9 . 325–331 . September 1993 . 7504360 . 10.1016/0165-6147(93)90005-5 .
  9. Kase Y, Yuizono T, Muto M . Piperidino Groups in Antitussive . Journal of Medicinal Chemistry . 6 . 2 . 118–122 . March 1963 . 14188779 . 10.1021/jm00338a007 .
  10. Cahusac PM, Senok SS, Hitchcock IS, Genever PG, Baumann KI . Are unconventional NMDA receptors involved in slowly adapting type I mechanoreceptor responses? . Neuroscience . 133 . 3 . 763–773 . May 2005 . 15908129 . 10.1016/j.neuroscience.2005.03.018 . 15610561 .
  11. Wallach J, Kavanagh PV, McLaughlin G, Morris N, Power JD, Elliott SP, Mercier MS, Lodge D, Morris H, Dempster NM, Brandt SD . 6 . Preparation and characterization of the 'research chemical' diphenidine, its pyrrolidine analogue, and their 2,2-diphenylethyl isomers . Drug Testing and Analysis . 7 . 5 . 358–367 . May 2015 . 25044512 . 10.1002/dta.1689 . 2019-12-10 . live . https://web.archive.org/web/20200307114648/http://researchonline.ljmu.ac.uk/id/eprint/3408/1/DTA-14-0117.R1.pdf . 2020-03-07 .
  12. Wallach J, Kang H, Colestock T, Morris H, Bortolotto ZA, Collingridge GL, Lodge D, Halberstadt AL, Brandt SD, Adejare A . 6 . Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues . PLOS ONE . 11 . 6 . e0157021 . 17 June 2016 . 27314670 . 4912077 . 10.1371/journal.pone.0157021 . free . 2016PLoSO..1157021W .
  13. Sahai MA, Davidson C, Dutta N, Opacka-Juffry J . Mechanistic Insights into the Stimulant Properties of Novel Psychoactive Substances (NPS) and Their Discrimination by the Dopamine Transporter-In Silico and In Vitro Exploration of Dissociative Diarylethylamines . Brain Sciences . 8 . 4 . 63 . April 2018 . 29642450 . 5924399 . 10.3390/brainsci8040063 . free .
  14. Wurita A, Hasegawa K, Minakata K, Watanabe K, Suzuki O . A large amount of new designer drug diphenidine coexisting with a synthetic cannabinoid 5-fluoro-AB-PINACA found in a dubious herbal product . August 2014 . Forensic Toxicology . 32 . 2 . 331–337 . 10.1007/s11419-014-0240-y. 25995354 .
  15. Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O . Postmortem distribution of AB-CHMINACA, 5-fluoro-AMB, and diphenidine in body fluids and solid tissues in a fatal poisoning case: usefulness of adipose tissue for detection of the drugs in unchanged forms . January 2015 . Forensic Toxicology . 33 . 1 . 45–53 . 10.1007/s11419-014-0245-6. 11884184 .
  16. Uchiyama N, Shimokawa Y, Kikura-Hanajiri R, Demizu Y, Goda Y, Hakamatsuka T . A synthetic cannabinoid FDU-NNEI, two 2H-indazole isomers of synthetic cannabinoids AB-CHMINACA and NNEI indazole analog (MN-18), a phenethylamine derivative N-OH-EDMA, and a cathinone derivative dimethoxy-α-PHP, newly identified in illegal products . Forensic Toxicology . 33 . 2 . 244–259 . July 2015 . 26257833 . 4525202 . 10.1007/s11419-015-0268-7 .
  17. Minakata K, Yamagishi I, Nozawa H, Hasegawa K, Wurita A, Gonmori K, Suzuki M, Watanabe K, Suzuki O . Diphenidine and its metabolites in blood and urine analyzed by MALDI-Q-TOF mass spectrometry . July 2015 . Forensic Toxicology . 33 . 2 . 402–408 . 10.1007/s11419-015-0273-x. 44007379 .
  18. Kudo K, Usumoto Y, Kikura-Hanajiri R, Sameshima N, Tsuji A, Ikeda N . A fatal case of poisoning related to new cathinone designer drugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and a dissociative agent, diphenidine . Legal Medicine . 17 . 5 . 421–426 . September 2015 . 26162997 . 10.1016/j.legalmed.2015.06.005 .
  19. Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18) . Arsenault D . Canada Gazette . 1 June 2016 . 150 . 11 . 2016-11-17 . 2017-12-02 . https://web.archive.org/web/20171202203151/http://www.gazette.gc.ca/rp-pr/p2/2016/2016-06-01/html/sor-dors106-eng.php . live .

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