Chemistry:Α-Pyrrolidinopentiophenone

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α-Pyrrolidinovalerophenone (α-PVP), also known as α-pyrrolidinopentiophenone , O-2387, β-keto-prolintane, prolintanone,[1][2] or desmethylpyrovalerone, colloquially, it is sometimes called flakka or gravel,[3][4] is a synthetic stimulant of the cathinone class developed in the 1960s that has been sold as a designer drug and often consumed for recreational reasons.[5][6][7] α-PVP is chemically related to pyrovalerone and is the ketone analog of prolintane.[8]

Use and effects

α-PVP is used by a variety of different routes of administration, including oral, insufflation, injection, vaporization, sublingual, and rectal.[5] The dose range of α-PVP for therapeutic purposes was originally defined as 10 to 50 mg, with a most-suitable dose of 20 mg, whereas the recreational dose range is typically between 10 and 300 mg.[5] The effects of α-PVP onset after 10 minutes, peak after 10 to 40 minutes, and last 2 to 3 hours.[5]

The effects of α-PVP include cocaine-like psychostimulant effects, euphoria, elevated mood, alertness, pleasurable rush, feeling "sped up", mania-like symptoms, enhanced energy, motivation and productivity, enhanced music enjoyment, mild sexual stimulation, insomnia, paranoia, hallucinations, and increased aggression and violence.[5] In emergency settings, commonly observed effects have included psychosis-like state, agitation, aggression, hallucinations, abnormal heart rate, and vomiting.[5] It also produces sympathomimetic effects, such as increased heart rate and blood pressure.[5]

Adverse effects

α-PVP, like other stimulants, can cause hyperstimulation, paranoia, and hallucinations.[9] α-PVP has been reported to be the cause, or a significant contributory cause of death in suicides and overdoses caused by combinations of drugs.[10][11][12][13] α-PVP has also been linked to at least one death with pulmonary edema and moderately advanced atherosclerotic coronary artery disease when it was combined with pentedrone.[14]

According to Craig Crespi in the journal Case Reports in Psychiatry, "symptoms are known to easily escalate into frightening delusions, paranoid psychosis, extreme agitation, and a multitude of other altered mental states." These common adverse effects of α-PVP are in line with other stimulants.[15]

Pharmacology

Pharmacodynamics

α-PVP acts as a potent norepinephrine–dopamine reuptake inhibitor (NDRI), similarly to other NDRIs like methylphenidate, cocaine, and methylenedioxypyrovalerone (MDPV).[5][16] Its IC50 values have been found to be 14 to 70 nM for norepinephrine reuptake inhibition and 13 to 80 nM for dopamine reuptake inhibition in rat brain synaptosomes and human embryonic kidney 293 (HEK293) cells expressing the monoamine transporters (MATs).[17][18][19][20] In contrast to its effects on catecholamine reuptake, α-PVP has negligible effects on serotonin reuptake.[5]

The drug is much more potent than amphetamine as an NDRI in in vitro, with 46-fold greater potency in terms of dopamine reuptake inhibition and 7-fold greater potency in terms of norepinephrine reuptake inhibition in HEK293 cells.[21] It is one of the most potent dopamine reuptake inhibitors in vitro known.[16]

Similarly to other cathinone, α-PVP has been shown to have stimulant-like effects (i.e., hyperlocomotion), reinforcing effects, and sympathomimetic effects in rodents.[5][22][23][24]

Pharmacokinetics

The absorption of α-PVP is very rapid.[5] In humans, the effects of the drug onset after 10 minutes, peak between 10 and 40 minutes, and last 2 to 3 hours.[5]

α-PVP is said to be highly lipophilic due to its pyrrolidine ring, which in turn is said to markedly enhance its ability to permeate the blood–brain barrier relative to other cathinones.[5]

The distribution, metabolism, and elimination of α-PVP have been studied.[5]

Chemistry

α-PVP gives no reaction with the Marquis reagent. It gives a grey/black reaction with the Mecke reagent.[25]

Detection in body fluids

α-PVP may be quantified in blood, plasma, or urine by liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalized patients or to provide evidence in a medicolegal death investigation. Blood or plasma α-PVP concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally, >100 μg/L in intoxicated patients, and >300 μg/L in victims of acute overdosage.[26][27]

History

α-PVP was first described in the literature in 1963.[5]

Society and culture

α-PVP is banned in Estonia, Finland, France, Germany, Hungary, Russia, Ireland, Latvia, Lithuania, Netherlands, Poland, Romania, Slovenia, Sweden, the United Kingdom, Turkey, Norway,[17] as well as the Czech Republic.[28]

Australia

α-PVP is a Schedule 9 prohibited substance under the Poisons Standard (July 2016).[29] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[29] The drug was explicitly made illegal in New South Wales after it was illegally marketed with the imprimatur of erroneous legal advice that it was not encompassed by analog provisions of the relevant act. It is encompassed by those provisions, and therefore has been illegal for many years in New South Wales. The legislative action followed the death of two individuals from using it; one jumping off a balcony, another having a heart attack after a state of delirium.[30][31]

China

As of October 2015, α-PVP is a controlled substance in China.[32]

European Union

α-PVP was required to be banned by EU member states by 3 July 2017.[33]

Italy

Cathinone and all structurally derived analogues (including pyrovalerone analogues) were classified as narcotics in January 2012.[34][17]

United States

On January 28, 2014, the U.S. Drug Enforcement Agency (DEA) listed α-PVP, along with nine other synthetic cathinones, as a Schedule I controlled substance with a temporary ban, effective February 27, 2014.[35] The temporary ban was then extended.[36]

Economics

α-PVP is sometimes the active ingredient in recreational drugs sold as "bath salts".[30] It may also be distinguished from "bath salts" and sold under a different name: "flakka," a name used in Florida, or "gravel" in other parts of the U.S. It is reportedly available as cheaply as US$5 per dose.[37] A laboratory for one county in Florida reported a steady rise in α-PVP detections in seized drugs from none in January–February 2014 to 84 in September 2014.[38]

See also

References

  1. ↑ "PubChem Substance Record for SID 481087126, alpha-PVP". National Center for Biotechnology Information. May 9, 2023. https://pubchem.ncbi.nlm.nih.gov/substance/481087126. 
  2. ↑ "PubChem Substance Record for SID 172113243, alpha-Pyrrolidinovalerophenone". National Center for Biotechnology Information. March 3, 2023. https://pubchem.ncbi.nlm.nih.gov/substance/172113243. 
  3. ↑ "'Zombie drug' flakka may have hit Winnipeg streets: police". CBC News. November 2, 2017. http://www.cbc.ca/news/canada/manitoba/zombie-drug-flakka-may-have-hit-winnipeg-streets-police-1.4383153. 
  4. ↑ "Flakka: What is the 'zombie drug' blamed for face-eating attacks?". The Independent. August 17, 2016. https://www.independent.co.uk/news/world/americas/flakka-what-is-it-florida-face-eating-attack-zombie-drug-austin-harrouff-a7195871.html. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 "DARK Classics in Chemical Neuroscience: α-Pyrrolidinovalerophenone ("Flakka")". ACS Chem Neurosci 10 (1): 168–174. January 2019. doi:10.1021/acschemneuro.8b00525. PMID 30384587. 
  6. ↑ "α-Pyrrolidinovalerophenones" GB patent 927475, published May 29, 1963
  7. ↑ "SOFT Designer Drug Committee Monographs: Alpha-PVP". Society of Forensic Toxicologists. September 13, 2013. http://www.soft-tox.org/files/Designer_Drugs/Alpha-PVP.pdf. 
  8. ↑ "New designer drug alpha-pyrrolidinovalerophenone (PVP): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques". Journal of Mass Spectrometry 44 (6): 952–64. June 2009. doi:10.1002/jms.1571. PMID 19241365. Bibcode: 2009JMSp...44..952S. 
  9. ↑ "Drugs of Abuse Emerging Trends". National Institute on Drug Abuse. 6 April 2015. http://www.drugabuse.gov/drugs-abuse/emerging-trends. 
  10. ↑ "Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results". Journal of Analytical Toxicology 37 (3): 135–46. April 2013. doi:10.1093/jat/bks136. PMID 23361867. 
  11. ↑ "t". AAFS Proceedings. 2013. Abstract K16. http://www.aafs.org/sites/default/files/pdf/ProceedingsWashingtonDC2013.pdf. Retrieved 2015-04-03. 
  12. ↑ "Cheap, synthetic 'flakka' dethroning cocaine on Florida drug scene". https://news.yahoo.com/cheap-synthetic-flakka-dethroning-cocaine-florida-drug-scene-140910992.html. "27 people have died from flakka-related overdoses in the last eight months in Broward County" 
  13. ↑ "Suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones: Case report of non-fatal intoxication with AB-CHMINACA, AB-FUBINACA, alpha-PHP, alpha-PVP and 4-CMC". Forensic Science International 265: 121–4. August 2016. doi:10.1016/j.forsciint.2016.01.018. PMID 26890319. 
  14. ↑ "A Fatal Case of Pentedrone and α-Pyrrolidinovalerophenone Poisoning". Journal of Analytical Toxicology 39 (4): 324–9. May 2015. doi:10.1093/jat/bkv011. PMID 25737339. 
  15. ↑ Crespi, Craig (June 22, 2016). "Flakka-Induced Prolonged Psychosis". Case Reports in Psychiatry (Wiley) 2016 (1): 1. doi:10.1155/2016/3460849. PMID 27418996. 
  16. ↑ 16.0 16.1 "Designer drugs: mechanism of action and adverse effects". Arch Toxicol 94 (4): 1085–1133. April 2020. doi:10.1007/s00204-020-02693-7. PMID 32249347. Bibcode: 2020ArTox..94.1085L. 
  17. ↑ 17.0 17.1 17.2 "EMCDDA–Europol Joint Report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP)". European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). September 2015. http://www.emcdda.europa.eu/publications/joint-reports/alpha-pvp. 
  18. ↑ "Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV)". Neuropharmacology 87: 206–213. December 2014. doi:10.1016/j.neuropharm.2014.02.016. PMID 24594476. 
  19. ↑ "Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones". European Neuropsychopharmacology 25 (3): 365–376. March 2015. doi:10.1016/j.euroneuro.2014.12.012. PMID 25624004. http://edoc.unibas.ch/56167/1/20170921162745_59c3cc617d4fd.pdf. 
  20. ↑ "1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors". Journal of Medicinal Chemistry 49 (4): 1420–1432. February 2006. doi:10.1021/jm050797a. PMID 16480278. 
  21. ↑ "Measuring inhibition of monoamine reuptake transporters by new psychoactive substances (NPS) in real-time using a high-throughput, fluorescence-based assay". Toxicol in Vitro 45 (Pt 1): 60–71. December 2017. doi:10.1016/j.tiv.2017.05.010. PMID 28506818. Bibcode: 2017ToxVi..45...60Z. 
  22. ↑ "Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats". Neuropharmacology 134 (Pt A): 28–35. May 2018. doi:10.1016/j.neuropharm.2017.08.018. PMID 28811192. 
  23. ↑ "Reinforcing effects of abused 'bath salts' constituents 3,4-methylenedioxypyrovalerone and α-pyrrolidinopentiophenone and their enantiomers". Behavioural Pharmacology 28 (7): 578–581. October 2017. doi:10.1097/FBP.0000000000000315. PMID 28570297. 
  24. ↑ "Stereoselective neurochemical, behavioral, and cardiovascular effects of α-pyrrolidinovalerophenone enantiomers in male rats". Addict Biol 25 (6). November 2020. doi:10.1111/adb.12842. PMID 31724254. 
  25. ↑ "Reactions table". Reagent Base. http://reagent-base.net/reagents-table/. 
  26. ↑ "Toxicity and death following recreational use of 2-pyrrolidino valerophenone". Clinical Toxicology 51 (9): 899–903. November 2013. doi:10.3109/15563650.2013.847187. PMID 24111554. 
  27. ↑ Disposition of toxic drugs and chemicals in man. Seal Beach, Ca.: Biomedical Publications. 2014. p. 1751. ISBN 978-0-9626523-9-4. 
  28. ↑ "Látky, o které byl doplněn seznam č. 4 psychotropních látek (příloha č. 4 k nařízení vlády č. 463/2013 Sb.)" (in cs). Ministerstvo zdravotnictví. https://www.mzcr.cz/Admin/_upload/files/3/Nov%C3%A9%20PL.pdf. 
  29. ↑ 29.0 29.1 Poisons Standard July 2016 Comlaw.gov.au
  30. ↑ 30.0 30.1 "'Bath salts' death: lethal drug was a top seller". The Sydney Morning Herald. http://www.smh.com.au/nsw/bath-salts-death-glenn-punchs-terrifying-end-20131008-2v5jp.html. 
  31. ↑ "Flakka, synthetic drug behind increasingly bizarre crimes". AP. 30 Apr 2015. http://bigstory.ap.org/article/f3667988d0e042cfbb9b40838a78ab65/naked-paranoids-begging-police-save-them-thats-flakka. 
  32. ↑ "Error: no |title= specified when using {{Cite web}}" (in zh). 27 September 2015. http://www.sfda.gov.cn/WS01/CL0056/130753.html. 
  33. ↑ Council Implementing Decision (EU) 2016/1070 of 27 June 2016 on subjecting 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-pyrrolidinovalerophenone, α-PVP) to control measures
  34. ↑ "Decreto 29 dicembre 2011 (12A00013) (G.U. Serie Generale n. 3 del 4 gennaio 2012)". http://www.politicheantidroga.it/media/491607/decreto%20ministero%20salute%2029%20dicembre%202011.pdf. 
  35. ↑ "Rules - 2014". http://www.deadiversion.usdoj.gov/fed_regs/rules/2014/fr0128.htm. 
  36. ↑ "Lists of:Scheduling Actions, Controlled Substances, Regulated Chemicals". August 2016. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf. 
  37. ↑ "Flakka: The New Illegal Drug You Need to Know About". Inc.. November 8, 2015. http://www.inc.com/joseph-steinberg/flakka-the-new-illegal-drug-you-need-to-know-about.html. 
  38. ↑ "Flakka: Rampant designer drug dubbed '$5 insanity'". Sun-Sentinel (Fort Lauderdale, Fla.). April 2, 2015. http://www.sun-sentinel.com/local/broward/fl-flakka-on-the-rise-20150402-story.html. 

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