Diphenidine

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Diphenidine
Diphenidine.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C19H23N
Molar mass 265.39 g/mol
3D model (JSmol)
Melting point 210 °C (410 °F)

Diphenidine (1,2-DEP, DPD, DND) is a dissociative anesthetic that has been sold as a designer drug.[1][2][3] 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.[1] Shortly after the 2013 UK ban on arylcyclohexylamines, diphenidine and the related compound methoxphenidine became available on the grey market.[1] Anecdotal reports describe high doses of diphenidine producing "bizarre somatosensory phenomena and transient anterograde amnesia."[1] Diphenidine and related diarylethylamines have been studied in vitro as treatments for neurotoxic injury and are antagonists of the NMDA receptor.[4][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.[6] 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.[5] 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.[1] Diphenidine's highest affinity is for the NMDA receptor, but it does display submicromolar affinity for the σ1 receptor, σ2 receptor and dopamine transporter.[11]

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.[12][13][14] The first reported seizure concerned a Japanese product called "fragrance powder" containing diphenidine and benzylpiperazine.[15] A herbal incense sold in the Shizuoka Prefecture under the name "Aladdin (sic) Spacial Edition" was found to contain diphenidine and 5F-AB-PINACA at concentrations of 289 mg/g and 55.5 mg/g, respectively.[12] A product called ‘‘Herbal Incense. The Super Lemon’’ containing AB-CHMINACA, 5F-AMB, and diphenidine was implicated in a fatal poisoning.[13] 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.[16]

In Canada, MT-45 and its analogues were made Schedule I controlled substances.[17] 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 DND 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[edit]

References[edit]

  1. ^ a b c d e Morris, H.; Wallach, J. (July–August 2014). "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis. 6 (7–8): 614–632. PMID 24678061. doi:10.1002/dta.1620. 
  2. ^ Wink, Carina S. D.; Michely, Julian A.; Jacobsen-Bauer, Andrea; Zapp, Josef; Maurer, Hans H. (1 January 2016). "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: 1005–1014. ISSN 1942-7611. PMID 26811026. doi:10.1002/dta.1946. 
  3. ^ Helander, Anders; Beck, Olof; Bäckberg, Matilda (28 May 2015). "Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine". Clinical Toxicology. 53 (5): 446–453. ISSN 1556-3650. PMID 25881797. doi:10.3109/15563650.2015.1033630. 
  4. ^ Nancy M. Gray; Brian K. Cheng (6 April 1994). "Patent EP 0346791 - 1,2-diarylethylamines for treatment of neurotoxic injury". G.D. Searle, LLC – via SureChEMBL. 
  5. ^ a b Berger, M. L.; Schweifer, A.; Rebernik, P.; Hammerschmidt, F. (May 2009). "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. PMID 19345586. doi:10.1016/j.bmc.2009.03.025. 
  6. ^ a b Wallach, J.; Kavanagh, P.; McLaughlin, G.; Morris, N.; Power, J.; Elliott, S.; Mercier, M.; Lodge, D.; Morris, H.; Dempster, N.; Brandt, S. (May 2015). "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. PMID 25044512. doi:10.1002/dta.1689. 
  7. ^ Leon Espinosa; Cécile Itzstein; Hervé Cheynel; Pierre D Delmas; Chantal Chenu (July 1999). "Active NMDA glutamate receptors are expressed by mammalian osteoclasts". The Journal of Physiology. 518 (1): 47–53. PMC 2269403Freely accessible. PMID 10373688. doi:10.1111/j.1469-7793.1999.0047r.x. 
  8. ^ Michael A. Rogawski (September 1993). "Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines". Trends in Pharmacological Sciences. 14 (9): 325–331. PMID 7504360. doi:10.1016/0165-6147(93)90005-5. 
  9. ^ Yoshitoshi Kasé; Tomokazu Yuizono; Mieko Muto (March 1961). "Piperidino Groups in Antitussive Activity". Journal of Medicinal Chemistry. 6 (2): 118–122. PMID 14188779. doi:10.1021/jm00338a007. 
  10. ^ Cahusac, P. M. B.; Senok, S. S.; Hitchcock, I. S.; Genever, P. G.; Baumann, K. I. (May 2005). "Are unconventional NMDA receptors involved in slowly adapting type I mechanoreceptor responses?". Neuroscience. 133 (3): 763–773. PMID 15908129. doi:10.1016/j.neuroscience.2005.03.018 – via ScienceDirect. 
  11. ^ Wallach, Jason; Kang, Heather; Colestock, Tristan; Morris, Hamilton; Bortolotto, Zuner A.; Collingridge, Graham L.; Lodge, David; Halberstadt, Adam L.; Brandt, Simon D.; Adejare, Adeboye (17 June 2016). "Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues". PLOS ONE. 11 (6): e0157021. ISSN 1932-6203. PMC 4912077Freely accessible. PMID 27314670. doi:10.1371/journal.pone.0157021. 
  12. ^ a b Amin Wurita; Koutaro Hasegawa; Kayoko Minakata; Kanako Watanabe; Osamu Suzuki (August 2014). "A large amount of new designer drug diphenidine coexisting with a synthetic cannabinoid 5-fluoro-AB-PINACA found in a dubious herbal product". Forensic Toxicology. 32 (2): 331–337. doi:10.1007/s11419-014-0240-y. 
  13. ^ a b Koutaro Hasegawa; Amin Wurita; Kayoko Minakata; Kunio Gonmori; Hideki Nozawa; Itaru Yamagishi; Kanako Watanabe; Osamu Suzuki (January 2015). "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". Forensic Toxicology. 33 (1): 45–53. doi:10.1007/s11419-014-0245-6. 
  14. ^ Nahoko Uchiyama; Yoshihiko Shimokawa; Ruri Kikura-Hanajiri; Yosuke Demizu; Yukihiro Goda; Takashi Hakamatsuka (July 2015). "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. PMC 4525202Freely accessible. PMID 26257833. doi:10.1007/s11419-015-0268-7. 
  15. ^ Kayoko Minakata; Itaru Yamagishi; Hideki Nozawa; Koutaro Hasegawa; Amin Wurita; Kunio Gonmori; Masako Suzuki; Kanako Watanabe; Osamu Suzuki (July 2015). "Diphenidine and its metabolites in blood and urine analyzed by MALDI-Q-TOF mass spectrometry". Forensic Toxicology. 33 (2): 402–408. doi:10.1007/s11419-015-0273-x. 
  16. ^ Keiko Kudo; Yosuke Usumoto; Ruri Kikura-Hanajiri; Naomi Sameshima; Akiko Tsuji; Noriaki Ikeda (September 2015). "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. PMID 26162997. doi:10.1016/j.legalmed.2015.06.005. 
  17. ^ Denis Arsenault (1 June 2016). "Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18)". Canada Gazette. Government of Canada. 150 (11).