Diphenidine (1,2-DEP,DPD,DND) is adissociativeanesthetic that has been sold as adesigner drug.[2][3][4]Diphenidine was first synthesized in 1924 using aBruylants reaction similar to the one later employed in the discovery ofphencyclidine in 1956.[2] Following the 2013 UK ban onarylcyclohexylamines, diphenidine and the related compoundmethoxphenidine emerged on thegrey market.[2] Anecdotal reports indicate that high doses of diphenidine can produce "bizarre somatosensory phenomena and transient anterograde amnesia."[2]
Electrophysiological studies show that diphenidine reduces the amplitude of NMDA-mediatedfEPSPs 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 thedopamine 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 theσ1 receptor,σ2 receptor, and dopamine transporter.[7][8]
Diphenidine and other diarylethylamines have been studied in vitro for their potential in treating neurotoxic injury. These compounds act as antagonists at theNMDA receptor.[9][6][5][10][11] In dogs, diphenidine demonstrates greater antitussive potency thancodeine phosphate.[12][13]
Since 2014, diphenidine has been detected in combination with other research chemicals, particularly synthetic cannabinoids and stimulants, in Japaneseherbal incense blends.[14][15][16] The first reported seizure involved a Japanese product labeled as "fragrance powder," which contained both diphenidine andbenzylpiperazine[17] A herbal incense product called "Aladdin Spacial [sic] Edition," sold inShizuoka Prefecture, was found to contain 289 mg/g of diphenidine and 55.5 mg/g of5F-AB-PINACA.[14] Another product,Herbal Incense. The Super Lemon, containingAB-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 threesubstituted cathinones, threebenzodiazepines, 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 theFood 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.
^abcdeMorris 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.PMID24678061.
^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.PMID26811026.
^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.PMID25881797.S2CID5962038.
^abBerger 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.PMID19345586.
^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.PMID7504360.
^Kase Y, Yuizono T, Muto M (March 1963). "Piperidino Groups in Antitussive".Journal of Medicinal Chemistry.6 (2):118–122.doi:10.1021/jm00338a007.PMID14188779.
^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.PMID15908129.S2CID15610561.
^abWurita 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.S2CID25995354.
^abHasegawa 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.S2CID11884184.
^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.S2CID44007379.
^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.PMID26162997.
