Diphenidine

{{Short description|Dissociative anesthetic designer drug}} {{Infobox drug | IUPAC_name = (±)-1-(1,2-Diphenylethyl)piperidine | image = Diphenidine.png | image_class = skin-invert-image

| tradename = | pregnancy_AU =  | pregnancy_US =  | pregnancy_category = | legal_status = | legal_AU = S9 | legal_BR = F2 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-07-24 |title=RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |url-status=live |archive-url=https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 |archive-date=2023-08-27 |access-date=2023-08-27 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-07-25}}</ref> | legal_CA = Schedule I | legal_DE = Anlage II | legal_UK = PSA | legal_UN = P II | routes_of_administration =  | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =  | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 36794-52-2 | ATC_prefix = | ATC_suffix = | PubChem = 206666 | KEGG = C22733 | ChEBI = 104234 | ChEMBL = 4303426 | ChemSpiderID = 179031 | UNII = H8Q4VPL82Y

| C = 19 | H = 23 | N = 1 | melting_point = 210 | smiles = c1ccc(cc1)CC(c2ccccc2)N3CCCCC3 | StdInChI = 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 | StdInChIKey = JQWJJJYHVHNXJH-UHFFFAOYSA-N }}

'''Diphenidine''' ('''1,2-DEP''', '''DPD''', '''DND''') is a dissociative anesthetic that has been sold as a designer drug.<ref name="Morris">{{cite journal | vauthors = Morris H, Wallach J | title = From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs | journal = Drug Testing and Analysis | volume = 6 | issue = 7–8 | pages = 614–632 | date = July–August 2014 | pmid = 24678061 | doi = 10.1002/dta.1620 }}</ref><ref>{{cite journal | vauthors = Wink CS, Michely JA, Jacobsen-Bauer A, Zapp J, Maurer HH | title = 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 | journal = Drug Testing and Analysis | volume = 8 | issue = 10 | pages = 1005–1014 | date = October 2016 | pmid = 26811026 | doi = 10.1002/dta.1946 }}</ref><ref>{{cite journal | vauthors = Helander A, Beck O, Bäckberg M | title = Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine | journal = Clinical Toxicology | volume = 53 | issue = 5 | pages = 446–453 | date = June 2015 | pmid = 25881797 | doi = 10.3109/15563650.2015.1033630 | s2cid = 5962038 }}</ref> Diphenidine was first synthesized in 1924 using a Bruylants reaction similar to the one later employed in the discovery of phencyclidine in 1956.<ref name="Morris"/> Following the 2013 UK ban on arylcyclohexylamines, diphenidine and the related compound methoxphenidine emerged on the grey market.<ref name="Morris"/> Anecdotal reports indicate that high doses of diphenidine can produce "bizarre somatosensory phenomena and transient anterograde amnesia."<ref name="Morris"/>

== Pharmacology ==

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.<ref name="Wallach">{{cite journal | vauthors = Wallach J, Kavanagh PV, McLaughlin G, Morris N, Power JD, Elliott SP, Mercier MS, Lodge D, Morris H, Dempster NM, Brandt SD | display-authors = 6 | title = Preparation and characterization of the 'research chemical' diphenidine, its pyrrolidine analogue, and their 2,2-diphenylethyl isomers | journal = Drug Testing and Analysis | volume = 7 | issue = 5 | pages = 358–367 | date = May 2015 | pmid = 25044512 | doi = 10.1002/dta.1689 | url = http://researchonline.ljmu.ac.uk/id/eprint/3408/1/DTA-14-0117.R1.pdf | access-date = 2019-12-10 | url-status = live | archive-url = https://web.archive.org/web/20200307114648/http://researchonline.ljmu.ac.uk/id/eprint/3408/1/DTA-14-0117.R1.pdf | archive-date = 2020-03-07 }}</ref> 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.<ref name="Berger"/> Since diphenidine's emergence in 2013, vendors have claimed it acts on the dopamine transporter, but supporting data only became available in 2016.<ref name="Morris"/> 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.<ref name="WallachPLOS">{{cite journal | vauthors = Wallach J, Kang H, Colestock T, Morris H, Bortolotto ZA, Collingridge GL, Lodge D, Halberstadt AL, Brandt SD, Adejare A | display-authors = 6 | title = Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues | journal = PLOS ONE | volume = 11 | issue = 6 | article-number = e0157021 | date = 17 June 2016 | pmid = 27314670 | pmc = 4912077 | doi = 10.1371/journal.pone.0157021 | doi-access = free | bibcode = 2016PLoSO..1157021W }}</ref><ref>{{cite journal | vauthors = Sahai MA, Davidson C, Dutta N, Opacka-Juffry J | title = 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 | journal = Brain Sciences | volume = 8 | issue = 4 | page = 63 | date = April 2018 | pmid = 29642450 | pmc = 5924399 | doi = 10.3390/brainsci8040063 | doi-access = free }}</ref>

== Research == 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.<ref>{{cite patent | url= https://patents.google.com/patent/EP0346791A1/en?oq=EP-0346791 | country = EP | number = 0346791 | title = 1,2-diarylethylamines for treatment of neurotoxic injury | assign = G.D. Searle, LLC | inventor = Gray NM, Cheng BK | gdate = 6 April 1994 }}</ref><ref name="Berger">{{cite journal | vauthors = Berger ML, Schweifer A, Rebernik P, Hammerschmidt F | title = NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds | journal = Bioorganic & Medicinal Chemistry | volume = 17 | issue = 9 | pages = 3456–3462 | date = May 2009 | pmid = 19345586 | doi = 10.1016/j.bmc.2009.03.025 }}</ref><ref name=Wallach/><ref>{{cite journal | vauthors = Espinosa L, Itzstein C, Cheynel H, Delmas PD, Chenu C | title = Active NMDA glutamate receptors are expressed by mammalian osteoclasts | journal = The Journal of Physiology | volume = 518 | issue = Pt 1 | pages = 47–53 | date = July 1999 | pmid = 10373688 | pmc = 2269403 | doi = 10.1111/j.1469-7793.1999.0047r.x }}</ref><ref>{{cite journal | vauthors = Rogawski MA | title = Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines | journal = Trends in Pharmacological Sciences | volume = 14 | issue = 9 | pages = 325–331 | date = September 1993 | pmid = 7504360 | doi = 10.1016/0165-6147(93)90005-5 }}</ref> In dogs, diphenidine demonstrates greater antitussive potency than codeine phosphate.<ref name="Kasé">{{cite journal | vauthors = Kase Y, Yuizono T, Muto M | title = Piperidino Groups in Antitussive | journal = Journal of Medicinal Chemistry | volume = 6 | issue = 2 | pages = 118–122 | date = March 1963 | pmid = 14188779 | doi = 10.1021/jm00338a007 }}</ref><ref>{{cite journal | vauthors = Cahusac PM, Senok SS, Hitchcock IS, Genever PG, Baumann KI | title = Are unconventional NMDA receptors involved in slowly adapting type I mechanoreceptor responses? | journal = Neuroscience | volume = 133 | issue = 3 | pages = 763–773 | date = May 2005 | pmid = 15908129 | doi = 10.1016/j.neuroscience.2005.03.018 | s2cid = 15610561 }}</ref>

== Illicit use == Since 2014, diphenidine has been detected in combination with other research chemicals, particularly synthetic cannabinoids and stimulants, in Japanese herbal incense blends.<ref name="Wurita">{{cite journal | vauthors = Wurita A, Hasegawa K, Minakata K, Watanabe K, Suzuki O | title=A large amount of new designer drug diphenidine coexisting with a synthetic cannabinoid 5-fluoro-AB-PINACA found in a dubious herbal product | date=August 2014 | journal=Forensic Toxicology | volume=32 | issue=2 | pages=331–337 | doi=10.1007/s11419-014-0240-y| s2cid=25995354 }}</ref><ref name="Hasegawa">{{cite journal | vauthors = Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Watanabe K, Suzuki O | title=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 | date=January 2015 | journal=Forensic Toxicology | volume=33 | issue=1 | pages=45–53 | doi=10.1007/s11419-014-0245-6| s2cid=11884184 }}</ref><ref name="Uchiyama">{{cite journal | vauthors = Uchiyama N, Shimokawa Y, Kikura-Hanajiri R, Demizu Y, Goda Y, Hakamatsuka T | title = A synthetic cannabinoid FDU-NNEI, two 2''H''-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 | journal = Forensic Toxicology | volume = 33 | issue = 2 | pages = 244–259 | date = July 2015 | pmid = 26257833 | pmc = 4525202 | doi = 10.1007/s11419-015-0268-7 }}</ref> The first reported seizure involved a Japanese product labeled as "fragrance powder," which contained both diphenidine and benzylpiperazine<ref name="Minakata">{{cite journal | vauthors = Minakata K, Yamagishi I, Nozawa H, Hasegawa K, Wurita A, Gonmori K, Suzuki M, Watanabe K, Suzuki O | title=Diphenidine and its metabolites in blood and urine analyzed by MALDI-Q-TOF mass spectrometry | date=July 2015 | journal=Forensic Toxicology | volume=33 | issue=2 | pages=402–408 | doi=10.1007/s11419-015-0273-x| s2cid=44007379 }}</ref> A herbal incense product called "Aladdin {{sic|nolink=yes|Spacial}} Edition," sold in Shizuoka Prefecture, was found to contain 289 mg/g of diphenidine and 55.5 mg/g of 5F-AB-PINACA.<ref name="Wurita"/> Another product, ''Herbal Incense. The Super Lemon'', containing AB-CHMINACA, 5F-AMB, and diphenidine, was linked to a fatal poisoning.<ref name="Hasegawa"/> 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.<ref name="Kudo">{{cite journal | vauthors = Kudo K, Usumoto Y, Kikura-Hanajiri R, Sameshima N, Tsuji A, Ikeda N | title = A fatal case of poisoning related to new cathinone designer drugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and a dissociative agent, diphenidine | journal = Legal Medicine | volume = 17 | issue = 5 | pages = 421–426 | date = September 2015 | pmid = 26162997 | doi = 10.1016/j.legalmed.2015.06.005 }}</ref>

In Canada, MT-45 and its analogues—including DPD—were added to Schedule I controlled substances in 2016.<ref>{{cite journal | url=http://www.gazette.gc.ca/rp-pr/p2/2016/2016-06-01/html/sor-dors106-eng.php | title=Regulations Amending the Food and Drug Regulations (Parts G and J — Lefetamine, AH-7921, MT-45 and W-18) | vauthors = Arsenault D | journal=Canada Gazette | date=1 June 2016 | volume=150 | issue=11 | access-date=2016-11-17 | archive-date=2017-12-02 | archive-url=https://web.archive.org/web/20171202203151/http://www.gazette.gc.ca/rp-pr/p2/2016/2016-06-01/html/sor-dors106-eng.php | url-status=live }}</ref> 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 == * AD-1211 * Ephenidine * NPDPA * Fluorolintane * Lanicemine * Lefetamine * Methoxphenidine (MXP) * MT-45 * Remacemide

== References == {{Reflist}}

Category:Designer drugs Category:Dissociative drugs Category:NMDA receptor antagonists Category:1-Piperidinyl compounds Category:1,2-Diarylethylamines