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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Tuesday, June 4, 2013

Pyrovalerone Derivatives: A Driving Force in the RC Market

Background Info:

In 1967, a series of N-pyrrolidino ketone compounds were patented. The primary compound of this series was 1-(methylphenyl)-2-(pyrrolidinyl)-pentanone, now more popularly known as pyrovalerone. Synonyms for pyrovalerone are Centroton, Thymergix, Valerophenone, O-2371, and of course PV.

The Parent Compound:

Out of all the known/patented pyrovalerone analogues, only the parent compound has been widely studied.
Studies of pyrovalerone form the basis of our understanding of its structural analogues. PV is listed in the US as a Schedule 5 Controlled Substance, and has been used in the clinical setting as an anorectic and wakefulness promoting agent. 

Pyrovalerone (and by extension, its derivatives) is a structural relative of the CNS stimulant cathinone, and can therefore be referred to as a substituted cathinone.

There are 2 key characteristics of pyrovalerones distinguishing them from immediate cathinone derivatives; 1) a tertiary amine rather than a primary or secondary amine, which is incorporated into a heterocyclic five membered, pyrrolidine ring system (4 carbon and 1 nitrogen). And 2) an extended five carbon backbone (affording a pentiophenone structure as opposed to a propiophenone).

In the 1960's Stille and Holliday confirmed stimulant activity of PV in animals. In 1971 it was shown to reduce chronic fatigue in humans. Later it was shown to inhibit NE reuptake and induce NE release in rat heart. A study in the 1990's observed the parallel between its locomotor stimulant activity and its dopamine transporter occupancy in mice. Note; NE = norepinephrine, DA = dopamine.

In 1969, the methylenedioxyphenyl analogue of pyrovalerone, now well known by the abbreviation MDPV, was patented by a pharmaceutical company known by Boehringer Ingelheim. MDPV was never marketed and remained an obscure stimulant until recently appearing as a popular designer drug.

In summary, PV, along with many analogues thereof, are known ligands for the monoamine transporters; with a preference for NET and DAT, and for the most part, negligible interaction with SERT systems. As a general rule, compounds of this class can be presumed to act as powerful CNS and cardiovascular stimulants.

Appearance of Obscure PV Analogues:

MDPV


In the mid-2000's, MDPV (mentioned in section 1 paragraph 5) appeared on the pseudo-legal market as a designer drug, being sold by names such as Cloud 9 and Supercoke. It was also the main constituent in the first generation of novelty "bath salts". Reading news reports from the time of peak popularity for these items, it becomes apparent that the one defining commonality amongst the walking-dead style anti-drug propaganda is the description of a paranoid/agitated state resembling the symptoms of amphetamine-psychosis. It's fair to say that most bath salt users who exhibited these bizarre, stereotypic behaviors were experiencing symptoms of amphetamine psychosis, caused in many cases by the MDPV in the bath salts they were consuming.

MDPV is simply an analogue of PV containing oxygen atoms at carbons 3 and 4 of the benzene ring, bound by a methylene bridge. MDPV, like pyrovalerone, is an NDRI, and in its pure form is a powerful CNS and cardiovascular stimulant. Based on anecdotal reports it is a potent reinforcer, and it also seems to be, relative to other sympathomimetic amines, particularly prone to inducing psychotomimetic symptoms (as is evident by the many stories, albeit dramatized, of bath-salt psychosis).

MDPV is still being synthesized by Chinese labs (China seems to be the main manufacturer and exporter of RC's), but has been rarely encountered in the US since late 2011, when it was classified as a Schedule 1 Controlled Substance, along with a number of other substituted cathinones (namely mephedrone and methylone).

MDPV carried a devoted legion of followers, (specifically heavier stimulant users who prefer the convenience of licit substances), and the 2011 federal ban left a major demand to be filled. Since this time, new PV analogues have appeared periodically, usually touted by the manufacturers as MDPV replacements (although the deepest of MDPV devotees tend to rate each subsequent PV compound as inferior to MDPV).

A-PVP

APVP was mentioned in the 1967 patent for pyrovalerone. It can be described chemically as 1-phenyl-2-
(pyrrolidinyl)-pentanone. Synonyms include O-2387, a-PVP, O-desmethylpyrovalerone, or APVP, or PVP.  No substantial body of research exists on the properties of a-PVP, although its metabolism and excretion patterns in rat urine have been documented. It is presumed to act as a CNS and cardiovascular stimulant.

APVP is simply the O-demethylation product of pyrovalerone. It appeared in the early 2010's and became a popular grey-market product following bans on MDPV. Its effects are reported to be more or less comparable to MDPV. It has seemed to remain the gold standard in terms of MDPV replacements.

Based on reports by users, APVP in its pure form produces powerful CNS/cardiovascular stimulation. Its effects are apparent in doses under 10mg.

A-PVT


A-PVT is an analogue of A-PVP where the benzene ring has been replaced with a thiophene ring. It can be referred to chemically as 1-(thiophenyl)-2-(pyrrolidinyl)-pentanone. Little to no research exists on the properties of A-PVT. 

The exchange of the phenyl ring for a thiophenyl ring in a PV compound was first documented by Lancelot, and was reported to result in compounds of similar potency as both dopamine and norepineprine reuptake inhibitors.

APVT has very recently appeared as an RC. While many US RC merchants have become reluctant to offer APVP (or substituted cathinones in general), APVT has been promoted as a viable alternative. Users have reported mild effects similar to APVP.

MPHP
\
MPHP is a homologue of pyrovalerone, with the only difference being the addition of an extra carbon (or
rather CH3 group) on the alkyl side chain, affording a 6 carbon hexane backbone. It can be referred to chemically as 1-(4-methylphenyl)-2-(pyrrolidinyl)-hexanone.

MPHP has been encountered in recent years as a designer drug, and is speculated to be the chemical dubbed by chinese labs as "PV4", derived from a new naming scheme for pyrovalerone analogues marketed as MDPV replacements. Use of MPHP has been linked with liver and kidney damage.

The general SAR pattern in the pyrovalerone series seems to be 'greater activity with a longer alkyl backbone', with the maximum chain length being seven carbons. The most potent compounds known in this series consist of a five (pentyl) or six (hexyl) carbon backbone.

Side note; MPHP is technically not a true "pyro-valerone", as it contains a lengthened chain, however it should still fall under the category of pyrollinyl ketones.

PV8

There has been a new RC appearing in recent weeks being referred to by manufacturers as "PV8". Manufacturers claim it is the "best MDPV replacement yet". Nothing is known about this compound, and only speculation (although from a semi-reputable source) exists as to what the structure actually is for PV8. The supposed chemical name is 1-phenyl-2-(pyrrolidinyl)-heptanone. If this is indeed the correct chemical then it contains an unusually long alkyl backbone (although still conforms to the rule of 7 carbons or less).

Naphyrone 

Naphyrone is a unique analogue of pyrovalerone. It appeared on the grey market as a replacement for mephedrone, a cathinone derived stimulant and entactogen. It can be referred to chemically as 1-napthylenyl-2-(pyrrolidinyl)-pentanone. Synonyms for naphyrone include O-2482 and napthylpyrovalerone. It was reported to be the ingredient behind a product sold as NRG-1, but later analyses confirmed that only a portion of NRG-1 samples actually contained naphyrone.

Naphyrone differs from pyrovalerone with the fusion of an additional benzene ring to carbons 3 and 4 of pyrovalerone's benzene ring, forming a napthyl feature.

Naphyrone is pharmacologically distinct from other pyrovalerones in that it shows significant affinity to all three monoamine transporters; it acts as a triple reuptake inhibitor, meaning that it inhibits the uptake of norepinephrine, dopamine, and serotonin. This was the only PV compound to show activity in nanomolar (nM) concentrations.

Naphyrone is a schedule 1 controlled substance in the United States.

Further Reading:

EMCDDA Synthetic Cathinones Profile

Pyrovalerone Analogues: A Promising Class of Monoamine Uptake Inhibitors

A Forensic Toxicologist's Review of Pyrovalerone Analogues and a Review of Federal CSA Legislation

DrugsForum - APVP Drug Info Page

Crystal-Chunk APVP

4 comments:

  1. Maybe worth mentioning, there was another related drug that used to be available medically outside of the US only; prolintane. alpha-PVP could actually be called beta-keto-prolintane/prolintanone as they are identical in structure except for alpha-PVP's additional beta ketone.

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