Download 4. Effects mechanism

Assessment form
Date 12.12.2014
Annex 4
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Register No
3363/06.08.00.10/2014
1. ------IND- 2014 0654 FIN EN- ------ 20150112 --- --- IMPACT
Narcotics Act (373/2008) Section 3a
SUBSTANCE
4-Fluoro-α-pyrollidinovalerophenone (4F-α-PVP) (1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)pentan1-one)
4-fluoro-α-pyrrolidinovalerofenon (4F-α-PVP) (1-(4-fluorofenyl)-2-(pyrrolidin-1-yl)pentan-1-on)
1. Name, synonyms, street name, CAS number
IUPAC: 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)pentan-1-one
Other names: 4-fluoro-α-PVP; 4F-PVP; 4-fluoro-α-2-(1-pyrrolidinyl)-Valerophenone; 4-fluoro-αpyrrolidinovalerophenone; O-2370
CAS: 850352-62-4
2. Molecular structure
C15H20FNO
Drug class: cathinones
Structurally similar: alpha-PVP, pyrovalerone
3. Physical properties
Physical state: white or yellow powder
Molecular weight: 249.33 g/mol
Lääkealan turvallisuus- ja kehittämiskeskus | Säkerhets- och utvecklingscentret för läkemedelsområdet | Finnish Medicines Agency
P.O. Box 55, 00034 FIMEA I Tel. 029 522 3341 I [email protected] I www.fimea.fi I Y-ID 0921536-6
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4. Effects mechanism
Based on its structure, 4F-alpha-PVP is a fluoro-derivative of alpha-PVP, which has been
classified as a narcotic. Based on its structure, the substance closely resembles pyrovalerone,
which has been classified as a narcotic. Cathinones, which are structurally similar to 4F-alphaPVP, cross the brain-blood barrier effectively. The central nervous system effects of molecules
similar to pyrovalerone work through the monoamine neurotransmitter system, that is, by
increasing the neurotransmitter activity of dopamine, noradrenaline and serotonin receptors.
Binding to dopamine and noradrenaline transporter proteins inhibits the reuptake of these
neurotransmitters into the nerve cell, increases the amount of neurotransmitters in the synaptic
cleft, thereby enhancing the transmission of dopamine and noradrenaline in the central nervous
system.
In-vitro tests have shown 4F-alpha-PVP to affect the monoaminergic system, particularly
dopamine transport. 4F-alpha-PVP binds effectively to the dopamine transporter protein (DAT)
and inhibits its activity (DAT Ki= 82.0 ± 25 nM; In comparison, α-PVP 33.7 ± 5.4 nM and cocaine
432 ± 29 nM). Likewise, the reuptake of dopamine is inhibited (IC50 185± 62 nM, in comparison, αPVP 52.3 ± 6.2 nM and cocaine 461 ± 46 nM). During in-vitro tests, 4F-alpha-PVP also binds to
the noradrenaline (NA) reuptake protein (NET) and inhibits the reuptake of noradrenaline into the
cell, although the effect on the noradrenaline metabolism is not as strong as on dopamine (NET Ki
=830±140 nM, in comparison α-PVP 199 ± 45 nM and cocaine 2150± 190 nM; IC50 NA reuptake
=171 ± 35 nM, in comparison, α-PVP 56,0 ± 13 nM and cocaine 378 ± 48 nM). The effect on the
serotonin system during in-vitro tests was not significant.
In user reports, the substance’s effects are compared to those of alpha-PVP, which is very similar
in structure. The effects of 4F-alpha-PVP are euphoria, and it is also a stimulant and energy
booster. Adverse effects suffered were headaches, heart palpitations and increased temperature.
As a central nervous stimulant increasing dopamine signalling, although without significant
serotonergic stimulation, 4F-alpha-PVP bears the potential for dependency and abuse.
5. Manufacture
The substance’ synthesis has been described in scientific literature.
6. Effective dosage, misuse dosages
According to user reports, abuse doses are usually 50-100 mg taken orally or 10-20 mg through
the nose or vaporised and inhaled.
7. Mixed use
In the death reported from Sweden, in addition to 4F-alpha-PVP, other psychoactive substances
(MT-45, flubromazepam, methadone) were identified in a post mortem blood sample. Reports
made by users indicate that new psychoactive substances are often tried in combination with
other stimulants.
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8. Health risks
Health risks to the individual
Based on the structural similarity and users’ reports, the health risks of 4F-alpha-PVP abuse are
comparable to those of other stimulants and especially pyrovalerone and alpha-PVP.
In the autumn of 2014, Sweden reported two deaths associated with the use of 4F-alpha-PVP. In
one of the cases, no other substances apart from 4F-alpha-PVP were identified in a post mortem
blood sample. In the other case, methadone, MT-45 and flubromazepam were also found in the
blood.
Based on experiments conducted with rats, the structurally very similar alpha-PVP is metabolised
through CYP2B6, CYP2C19, CYP2D6 and CYP1A2 enzymes. It is possible that medicines
inhibiting these enzymes (e.g. several anti-depressants and epilepsy drugs) impede the
metabolism of alpha-PVP, thereby increasing and lengthening its effects. Due to the structural
similarity, it is very likely that the same risks apply to 4F-alpha-PVP.
Public health and social risks
The national health and social risks of 4F-alpha-PVP are comparable to those of similar narcotic
substances. In addition, the substance’s chemical structure and in-vitro results suggest a high
potential for abuse and addiction. Drug use is often related to the risk of social marginalisation and
the neglect of social responsibilities
9. Connection with other criminality
No data available
10. Documented observations on substance use
Medical and industrial use
There is no known medicinal or industrial use for the substance.
Reported appearance in Finland
Data reported by customs laboratory
First find 23.3.2013
2014: 5 samples, with a total of 171.0 g.
Data reported by the police crime laboratory
First finds in April 2014. A total of 5 crime reports, 8 samples, 14 g. Helsinki, southwest
Finland, Ostrobothnia, central Finland.
There is a user base for MDPV and alpha-PVP, so upon the availability of a substance with similar
effects, it can be assumed that demand in the market already exists.
Reporting in the EU and the EMCDDA Early Warning System (EWS)
4F-alpha-PVP was first reported to the EWS system from Sweden in February 2014 and after that
also from other countries (Table 1).
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Table 1
Seizures and other observations reported to the EWS system
Country
and date
Sweden
5.2.2014
Finland
5.5.2014
Amount and form
Official
25 g white powder
Police seizure
140 g white powder
Romania
27.6.2014
Latvia
30.9.2014
Sweden
1.10.2014
2.5 g yellow powder
Customs
inspection,
Helsinki
Police seizure
< 1 g white powder
Police seizure
NFP
Other information
Traveller from Malaga, Spain
Two deaths where 4F-alpha-PVP was
suspected to have played a role
11. Availability
The substance is available on the Internet.
12. Usage profile
Judging by Internet chat forums, users experimenting with new central nervous system stimulants
often have a background of using other stimulants, but new substances beyond control also pique
the interest of casual users.
13. Current status
4F-alpha-PVP is a controlled substance in Latvia. In Sweden, it was proposed on 10.11.2014 to
classify the substance as a narcotic.
14. Other information
4F-alpha-PVP’s ability to inhibit monoamine reuptake into the cell and thereby increase their
amount in the synaptic cleft resembles the effects mechanism of known stimulants. Consequently,
the substance’s abuse potential can be considered high. Since its use also involves serious health
risks, its spread and availability should be restricted.
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15. References
EDND. EMCDDA, 2014. Password protected official database (viewed 13.11.2014)
Data reported by customs laboratory. (E-mail communication 10.11.2014)
Data reported by the police crime laboratory. (E-mail communication 28.10.2014.)
Simmler LD, Buser TA, Conzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti
ME. Pharmacological characterization of designer cathinones in vitro. Br.J.Pharmacol. 2012; Epub
online Aug 17, 2012.
5. Meltzer PC, Butler D, Deschamps JR, Madras BK. 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one
(Pyrovalerone) Analogues: A Promising Class of Monoamine Uptake Inhibitors. Journal of Medicinal
Chemistry. 2006; 49:1420-1432.
6. Internet chat forums, user reports
http://www.chemsrus.com/forum/6-stimulants/20844-4f-pvp (viewed 13.11.2014)
https://www.drugs-forum.com/forum/showthread.php?t=226465 (viewed 13.11.2014)
7. https://www.flashback.org/t2228659 (viewed 13.11.2014)
8. Sauer C., et al. New designer drug alpha-pyrrolidinovalerophenone (PVP): studies on its metabolism
and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques, J
Mass Spectrom. 2009; 44:952-64
9. Chemicals Register. Finnish Safety and Chemicals Agency (Tukes). (viewed 2.12.2014)
10. Internet shops
Cayman Chemical,
https://www.caymanchem.com/app/template/Product.vm/catalog/15166;jsessionid=221E8E0207597
F93D7CA315DBA41E297 (viewed 13.11.2014)
Nordic RC, http://nordicrc.com/4f-pvp (viewed 13.11.2014)
11. Substanser under utredning. [Swedish] Folkhälsomyndigheten [Swedish], Sweden.
http://www.folkhalsomyndigheten.se/amnesomraden/tillsyn-och-regelverk/klassificering-avmissbrukssubstanser/substanser-under-utredning/ (viewed 13.11.2014)
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16. Alternatives to classification as an intoxicating substance and classification proposal
resulting from evaluation
Based on reports on the substance, the Finnish Medicines Agency recommends that the
substance be added to Annex IV to Government Decree (543/2008) on substances, preparations
and plants to be deemed narcotics.