Diphenidine

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Diphenidine
Diphenidine.svg
Identifiers
CAS Number
  • 36794-52-2 ☑Y
PubChem CID
  • 206666
ChemSpider
  • 179031
UNII
  • H8Q4VPL82Y
Chemical and physical data
Formula C19H23N
Molar mass 265.39 g/mol g·mol−1
3D model (JSmol)
  • Interactive image
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][12]

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.[13][14][15] The first reported seizure concerned a Japanese product called "fragrance powder" containing diphenidine and benzylpiperazine.[16] 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.[13] A product called ‘‘Herbal Incense. The Super Lemon’’ containing AB-CHMINACA, 5F-AMB, and diphenidine was implicated in a fatal poisoning.[14] 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.[17]

In Canada, MT-45 and its analogues were made Schedule I controlled substances.[18] 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

References

  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. doi:10.1002/dta.1620. PMID 24678061.
  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 (10): 1005–1014. doi:10.1002/dta.1946. ISSN 1942-7611. PMID 26811026.
  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. doi:10.3109/15563650.2015.1033630. ISSN 1556-3650. PMID 25881797.
  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. doi:10.1016/j.bmc.2009.03.025. PMID 19345586.
  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. doi:10.1002/dta.1689. PMID 25044512.
  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. doi:10.1111/j.1469-7793.1999.0047r.x. PMC 2269403. PMID 10373688.
  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. doi:10.1016/0165-6147(93)90005-5. PMID 7504360.
  9. ^ Yoshitoshi Kasé; Tomokazu Yuizono; Mieko Muto (March 1961). "Piperidino Groups in Antitussive Activity". Journal of Medicinal Chemistry. 6 (2): 118–122. doi:10.1021/jm00338a007. PMID 14188779.
  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. doi:10.1016/j.neuroscience.2005.03.018. PMID 15908129 – 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. doi:10.1371/journal.pone.0157021. ISSN 1932-6203. PMC 4912077. PMID 27314670.
  12. ^ Sahai, Michelle A.; Davidson, Colin; Dutta, Neelakshi; Opacka-Juffry, Jolanta (7 April 2018). "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. doi:10.3390/brainsci8040063. PMID 29642450.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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. doi:10.1007/s11419-015-0268-7. PMC 4525202. PMID 26257833.
  16. ^ 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.
  17. ^ 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. doi:10.1016/j.legalmed.2015.06.005. PMID 26162997.
  18. ^ 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. 150 (11).
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