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.

See also

Related Research Articles

<span class="mw-page-title-main">APINACA</span> Chemical compound

APINACA (AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide) is a drug that acts as a reasonably potent agonist for the cannabinoid receptors. It is a full agonist at CB1 with an EC50 of 142 nM and Ki of 3.24 nM (compared to the Ki of Δ9-THC at 28.35 nM and JWH-018 at 9.62 nM), while at CB2 it acts as a partial agonist with an EC50 of 141 nM and Ki of 1.68 nM (compared to the Ki of Δ9-THC at 37.82 nM and JWH-018 at 8.55 nM). Its pharmacological characterization has also been reported in a discontinued patent application. It had never previously been reported in the scientific or patent literature, and was first identified by laboratories in Japan in March 2012 as an ingredient in synthetic cannabis smoking blends, along with a related compound APICA. Structurally, it closely resembles cannabinoid compounds from a University of Connecticut patent, but with a simple pentyl chain on the indazole 1-position, and APINACA falls within the claims of this patent despite not being disclosed as an example.

<span class="mw-page-title-main">AB-FUBINACA</span> Chemical compound

AB-FUBINACA is a psychoactive drug that acts as a potent agonist for the cannabinoid receptors, with Ki values of 0.9 nM at CB1 and 23.2 nM at CB2 and EC50 values of 1.8 nM at CB1 and 3.2 nM at CB2. It was originally developed by Pfizer in 2009 as an analgesic medication but was never pursued for human use. In 2012, it was discovered as an ingredient in synthetic cannabinoid blends in Japan, along with a related compound AB-PINACA, which had not previously been reported.

<span class="mw-page-title-main">AB-PINACA</span> Chemical compound

AB-PINACA is a compound that was first identified as a component of synthetic cannabis products in Japan in 2012.

<span class="mw-page-title-main">ADBICA</span> Group of stereoisomers

ADBICA (also known as ADB-PICA) is a designer drug identified in synthetic cannabis blends in Japan in 2013. ADBICA had not previously been reported in the scientific literature prior to its sale as a component of synthetic cannabis blends. ADBICA features a carboxamide group at the 3-indole position, like SDB-001 and STS-135. The stereochemistry of the tert-butyl side-chain in the product is unresolved, though in a large series of indazole derivatives structurally similar to ADBICA that are disclosed in Pfizer patent WO 2009/106980, activity resides exclusively in the (S) enantiomers. ADBICA is a potent agonist of the CB1 receptor and CB2 receptor with an EC50 value of 0.69 nM and 1.8 nM respectively.

<span class="mw-page-title-main">Methoxphenidine</span> Chemical compound

Methoxphenidine is a dissociative of the diarylethylamine class that has been sold online as a designer drug. Methoxphenidine was first reported in a 1989 patent where it was tested as a treatment for neurotoxic injury. Shortly after the 2013 UK ban on arylcyclohexylamines methoxphenidine and the related compound diphenidine became available on the gray market, where it has been encountered as a powder and in tablet form. Though diphenidine possesses higher affinity for the NMDA receptor, anecdotal reports suggest methoxphenidine has greater oral potency. Of the three isomeric anisyl-substituents methoxphenidine has affinity for the NMDA receptor that is higher than 4-MeO-Diphenidine but lower than 3-MeO-Diphenidine, a structure–activity relationship shared by the arylcyclohexylamines.

<span class="mw-page-title-main">AB-CHMINACA</span> Chemical compound

AB-CHMINACA is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor (Ki = 0.78 nM) and CB2 receptor (Ki = 0.45 nM) and fully substitutes for Δ9-THC in rat discrimination studies, while being 16x more potent. Continuing the trend seen in other cannabinoids of this generation, such as AB-FUBINACA and AB-PINACA, it contains a valine amino acid amide residue as part of its structure, where older cannabinoids contained a naphthyl or adamantane residue.

<span class="mw-page-title-main">5F-ADB</span> Chemical compound

5F-ADB (also known as 5F-MDMB-PINACA) is an indazole-based synthetic cannabinoid from the indazole-3-carboxamide family, which has been used as an active ingredient in synthetic cannabis products and has been sold online as a designer drug. 5F-ADB is a potent agonist of the CB1 receptor, though it is unclear whether it is selective for this target. 5F-ADB was first identified in November 2014 from post-mortem samples taken from an individual who had died after using a product containing this substance. Subsequent testing identified 5F-ADB to have been present in a total of ten people who had died from unexplained drug overdoses in Japan between September 2014 and December 2014. 5F-ADB is believed to be extremely potent based on the very low levels detected in tissue samples, and appears to be significantly more toxic than earlier synthetic cannabinoid drugs that had previously been sold.

<span class="mw-page-title-main">ADB-CHMINACA</span> Chemical compound

ADB-CHMINACA (also known as MAB-CHMINACA) is an indazole-based synthetic cannabinoid. It is a potent agonist of the CB1 receptor with a binding affinity of Ki = 0.289 nM and was originally developed by Pfizer in 2009 as an analgesic medication. It was identified in cannabinoid blends in Japan in early 2015.

<span class="mw-page-title-main">Ephenidine</span> Dissociative anesthetic designer drug

Ephenidine is a dissociative anesthetic that has been sold online as a designer drug. It is illegal in some countries as a structural isomer of the banned opioid drug lefetamine, but has been sold in countries where it is not yet banned.

<span class="mw-page-title-main">Fluorolintane</span> Chemical compound

Fluorolintane is a dissociative anesthetic drug that has been sold online as a designer drug.

<span class="mw-page-title-main">5F-AMB</span> Chemical compound

5F-AMB (also known as 5F-MMB-PINACA and 5F-AMB-PINACA) is an indazole-based synthetic cannabinoid from the indazole-3-carboxamide family, which has been used as an active ingredient in synthetic cannabis products. It was first identified in Japan in early 2014. Although only very little pharmacological information about 5F-AMB itself exists, its 4-cyanobutyl analogue (instead of 5-fluoropentyl) has been reported to be a potent agonist for the CB1 receptor (KI = 0.7 nM).

<span class="mw-page-title-main">MDMB-CHMICA</span> Chemical compound

MDMB-CHMICA is an indole-based synthetic cannabinoid that is a potent agonist of the CB1 receptor and has been sold online as a designer drug. While MDMB-CHMICA was initially sold under the name "MMB-CHMINACA", the compound corresponding to this code name (i.e. the isopropyl instead of t-butyl analogue of MDMB-CHMINACA) has been identified on the designer drug market in 2015 as AMB-CHMINACA.

<span class="mw-page-title-main">NM-2201</span> Chemical compound

NM-2201 (also known as CBL-2201) is an indole-based synthetic cannabinoid that presumably has similar properties to the closely related 5F-PB-22 and NNE1, which are both full agonists and unselectively bind to CB1 and CB2 receptors with low nanomolar affinity.

<span class="mw-page-title-main">PX-1</span> Chemical compound

PX-1 is an indole-based synthetic cannabinoid that has been sold online as a designer drug.

<span class="mw-page-title-main">PX-2</span> Chemical compound

PX-2 is an indazole-based synthetic cannabinoid that has been sold online as a designer drug. It contains a phenylalanine amino acid amide as part of its structure.

<span class="mw-page-title-main">FUB-APINACA</span> Chemical compound

FUB-APINACA (also known as A-FUBINACA according to the EMCCDA framework for naming synthetic cannabinoids and FUB-AKB48) is an indazole-based synthetic cannabinoid that is presumed to be a potent agonist of the CB1 receptor and has been sold online as a designer drug. It is an analog of APINACA and 5F-APINACA where the pentyl chain has been replaced with fluorobenzyl.

<span class="mw-page-title-main">Indapyrophenidone</span> Chemical compound

Indapyrophenidone is a synthetic drug of the cathinone class that has been sold online as a designer drug.

<span class="mw-page-title-main">ADB-BINACA</span> Chemical compound

ADB-BINACA is a cannabinoid designer drug that has been found as an ingredient in some synthetic cannabis products. It was originally developed by Pfizer as a potential analgesic, and is a potent agonist of the CB1 receptor with a binding affinity (Ki) of 0.33 nM and an EC50 of 14.7 nM.

<span class="mw-page-title-main">ADB-BUTINACA</span> Chemical compound

ADB-BUTINACA is a synthetic cannabinoid compound which has been sold as a designer drug. It is a potent CB1 agonist, with a binding affinity of 0.29nM for CB1 and 0.91nM for CB2, and an EC50 of 6.36 nM for CB1.

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.
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