Diphenidine

Last updated
Diphenidine
Diphenidine.svg
Legal status
Legal status
Identifiers
  • (±)-1-(1,2-Diphenylethyl)piperidine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C19H23N
Molar mass 265.400 g·mol−1
3D model (JSmol)
Melting point 210 °C (410 °F)
  • c1ccc(cc1)CC(c2ccccc2)N3CCCCC3
  • InChI=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
  • Key: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] [9] In dogs diphenidine exhibits greater antitussive potency than codeine phosphate. [10] [11]

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. [7] 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 Spacial[sic] 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.

A related drug called IDDC is also available in the literature. [20] [21] This pharmaceutical entity is also made from 1,2-diphenylethylamine and also behaves as an NMDA antagonist.

See also

References

  1. ↑ Anvisa (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] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. 1 2 3 4 5 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.
  3. ↑ Wink CS, Michely JA, Jacobsen-Bauer A, Zapp J, Maurer HH (October 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. PMID   26811026.
  4. ↑ Helander A, Beck O, Bäckberg M (June 2015). "Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine". Clinical Toxicology. 53 (5): 446–453. doi:10.3109/15563650.2015.1033630. PMID   25881797. S2CID   5962038.
  5. ↑ EP 0346791,Gray NM, Cheng BK,"1,2-diarylethylamines for treatment of neurotoxic injury",issued 6 April 1994, assigned to G.D. Searle, LLC
  6. 1 2 Berger ML, 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.
  7. 1 2 Wallach J, Kavanagh PV, McLaughlin G, Morris N, Power JD, Elliott SP, et al. (May 2015). "Preparation and characterization of the 'research chemical' diphenidine, its pyrrolidine analogue, and their 2,2-diphenylethyl isomers" (PDF). Drug Testing and Analysis. 7 (5): 358–367. doi:10.1002/dta.1689. PMID   25044512. Archived (PDF) from the original on 2020-03-07. Retrieved 2019-12-10.
  8. ↑ Espinosa L, Itzstein C, Cheynel H, Delmas PD, Chenu C (July 1999). "Active NMDA glutamate receptors are expressed by mammalian osteoclasts". The Journal of Physiology. 518 (Pt 1): 47–53. doi:10.1111/j.1469-7793.1999.0047r.x. PMC   2269403 . PMID   10373688.
  9. ↑ Rogawski MA (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.
  10. ↑ Kase Y, Yuizono T, Muto M (March 1963). "Piperidino Groups in Antitussive". Journal of Medicinal Chemistry. 6 (2): 118–122. doi:10.1021/jm00338a007. PMID   14188779.
  11. ↑ Cahusac PM, Senok SS, Hitchcock IS, Genever PG, Baumann KI (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. S2CID   15610561.
  12. ↑ Wallach J, Kang H, Colestock T, Morris H, Bortolotto ZA, Collingridge GL, et al. (17 June 2016). "Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues". PLOS ONE. 11 (6): e0157021. Bibcode:2016PLoSO..1157021W. doi: 10.1371/journal.pone.0157021 . PMC   4912077 . PMID   27314670.
  13. ↑ Sahai MA, Davidson C, Dutta N, Opacka-Juffry J (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 . PMC   5924399 . PMID   29642450.
  14. 1 2 Wurita A, Hasegawa K, Minakata K, Watanabe K, Suzuki O (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. S2CID   25995354.
  15. 1 2 Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O (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. S2CID   11884184.
  16. ↑ Uchiyama N, Shimokawa Y, Kikura-Hanajiri R, Demizu Y, Goda Y, Hakamatsuka T (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.
  17. ↑ Minakata K, Yamagishi I, Nozawa H, Hasegawa K, Wurita A, Gonmori K, Suzuki M, Watanabe K, Suzuki O (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. S2CID   44007379.
  18. ↑ Kudo K, Usumoto Y, Kikura-Hanajiri R, Sameshima N, Tsuji A, Ikeda N (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.
  19. ↑ Arsenault D (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). Archived from the original on 2017-12-02. Retrieved 2016-11-17.
  20. ↑ Eckard Weber, John Keana, & Peter Barmettler, WO1990012575 (Oregon State Board of Higher Education, Oregon State).
  21. ↑ Gee KR, Barmettler P, Rhodes MR, McBurney RN, Reddy NL, Hu LY, Cotter RE, Hamilton PN, Weber E, Keana JF. 10,5-(Iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and derivatives. Potent PCP receptor ligands. J Med Chem. 1993 Jul 9;36(14):1938-46. doi: 10.1021/jm00066a002. PMID: 8101572.
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