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Diphenidine

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Diphenidine
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
FormulaC19H23N
Molar mass265.400 g·mol−1
3D model (JSmol)
Melting point210 °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] Diphenidine was first synthesized in 1924 using a Bruylants reaction similar to the one later employed in the discovery of phencyclidine in 1956.[2] Following the 2013 UK ban on arylcyclohexylamines, diphenidine and the related compound methoxphenidine emerged on the grey market.[2] Anecdotal reports indicate that high doses of diphenidine can produce "bizarre somatosensory phenomena and transient anterograde amnesia."[2]

Pharmacology

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Electrophysiological studies show that diphenidine reduces the amplitude of NMDA-mediated fEPSPs to a similar extent as ketamine, although its antagonistic effect has a slower onset.[5] The drug's two enantiomers exhibit markedly different NMDA receptor affinities, with the (S)-enantiomer being approximately 40 times more potent than the (R)-enantiomer.[6] Since diphenidine's emergence in 2013, vendors have claimed it acts on the dopamine transporter, but supporting data only became available in 2016.[2] While diphenidine shows the highest affinity for the NMDA receptor, it also binds with submicromolar affinity to the σ1 receptor, σ2 receptor, and dopamine transporter.[7][8]

Research

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Diphenidine and other diarylethylamines have been studied in vitro for their potential in treating neurotoxic injury. These compounds act as antagonists at the NMDA receptor.[9][6][5][10][11] In dogs, diphenidine demonstrates greater antitussive potency than codeine phosphate.[12][13]

Illicit use

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Since 2014, diphenidine has been detected in combination with other research chemicals, particularly synthetic cannabinoids and stimulants, in Japanese herbal incense blends.[14][15][16] The first reported seizure involved a Japanese product labeled as "fragrance powder," which contained both diphenidine and benzylpiperazine[17] A herbal incense product called "Aladdin Spacial [sic] Edition," sold in Shizuoka Prefecture, was found to contain 289 mg/g of diphenidine and 55.5 mg/g of 5F-AB-PINACA.[14] Another product, Herbal Incense. The Super Lemon, containing AB-CHMINACA, 5F-AMB, and diphenidine, was linked to a fatal poisoning.[15] More recently, diphenidine was implicated in a fatal case involving the simultaneous use of three substituted cathinones, three benzodiazepines, and alcohol, consumed through "bath salt" and "liquid aroma" products in Japan.[18]

In Canada, MT-45 and its analogues—including DPD—were added to Schedule I controlled substances in 2016.[19] Possession without proper authorization may result in a maximum penalty of seven years' imprisonment. That same year, Health Canada amended the Food and Drug Regulations to explicitly classify DPD as a restricted drug. Possession is limited to law enforcement agencies, individuals with exemption permits, or institutions with ministerial authorization.

See also

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References

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  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. ^ 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.
  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. ^ a b 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.
  6. ^ a b 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. ^ 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.
  8. ^ 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.
  9. ^ EP 0346791, Gray NM, Cheng BK, "1,2-diarylethylamines for treatment of neurotoxic injury", issued 6 April 1994, assigned to G.D. Searle, LLC 
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ a b 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. ^ a b 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.
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