The new synthetic cannabinoids on the block

Since approximately 2007, quinoline cannabinoid derivatives have been evaluated for cannabinoid receptor affinity.  A few studies have demonstrated a handful of compounds with the quinoline structure to be highly selective for the CB2 receptor over the CB1 receptor.

PB-22 and 5F-PB-22 are two emerging synthetic cannabinoid substances of this quinoline class.  They have been analytically confirmed as adulterants in herbal incense blends in the USA.

PB-22’s chemical name is 1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C23H22N2O2 and formula weight is 358.4 g/mol.  The chemical structure features an indole group, a pentyl alkyl chain, a carbonyl group and a 8-hydroxyquinoline moiety.

5F-PB-22’s chemical name is 1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C23H21FN2O2 and formula weight is 376.4 g/mol.  It features the same chemical structure as PB-22 with the exception of a single fluorine atom at the terminal carbon of the pentyl chain.

BB-22’s chemical name is 1-(cyclohexylmethyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C25H24N2O2 and formula weight is 384.5 g/mol.  It features the same chemical structure as PB-22 with the exception of the replacement of the pentyl alkyl chain with a cyclohexylmethyl moiety.

I am currently in the midwest traveling, so I thought I would look up these substances and see if they are controlled at the state level.  They are not controlled in any of the several midwestern states as schedule I drugs.  They are also not included in the updated list of controlled compounds in the legislation pending in any midwestern state.  In fact, I do not know of any location in the USA (state and/or federal) in which they are controlled explicitly.  It would also prove difficult to make these an analog case as they are significantly different (my scientific opinion) than JWH-018 or other controlled synthetic cannabinoids.   It is also of importance that these substances have no published in vitro or animal modeling data regarding their pharmacological activity at the receptor. 

Goodbye UR-144 and XLR-11.  Welcome the next wave of synthetic cannabinoids…the quinoline derivatives.  Meet the new boss, same as the old boss - more unknown than the preceding generations.

PS. Note reference 4 – not only the quinoline derivatives are listed, but also isoquinoline, quinoxaline, and quinazoline derivaties exist as well.

The cat and mouse games will continue!

References

1.    C Manera, V Benetti, MP Castelli et al. Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J Med Chem (2006) 49(20):  5947-5957.  PMID:  17004710

2.    C Manera, MG Cascio, V Benetti et al. New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists. Bioorg Med Chem Lett (2007) 17(23): 6505-6510.  PMID: 17942307

3.    R Saari, JC Torma, T Nevalainen. Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists. Bioorg Med Chem (2011) 19(2): 939-950. PMID: 21215643

4.    PG Baraldi, G Saponaro, AR Moorman et al. 7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as selective CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists. J Med Chem (2012) 55(14): 6608-6623.  PMID 22738271

The comfort zone

As a scientist, I am all too familiar with my comfort zone.  You know, that area that we like to exist within, the one that feels good, is "normal" and relatively stress free...

Well, I had to step outside that zone today.  In a big way.  I generally exist in a little lab bubble with my drugs, my instrumentation and my work only exiting for a court room appearance or client education on forensic toxicology...it's a relatively stress and anxiety free environment (at least most of the time unless there is a malfunctioning mass spec to troubleshoot at 4 pm on a Friday afternoon or a troublesome attorney relentlessly badgering you on the witness stand) .

Cue Imperial Death March...

And you know what? I stepped outside it and I was fine. I excelled.  And that feels really good, not only professionally, but also personally.  This is the way we continually improve as when we are out of our element, we learn the most about ourselves.  And after-all, isn't that what Science is at its core?

Cue Superman March...

Onward and upward.

Cheers.  

Folks, TV shows ain't the real world.

Hey folks, TV shows ain't the real world!

Something for your amusement.  I had posted this a while back on my personal Facebook account.  It is a screen shot of a mass spectrum used in the TV show, NCIS.  Please look at the text.  Hold back laughter.

Sorry for the clarity - the lighting in the room wasn't the greatest.

Even though it doesn't really make sense, I still want this mass spec! The sample that was analyzed was gastric contents of a decedent. It identifies "chicken stock", coffee, and cocoa! Also it identified some random water, "protein", and of course a mass spectrometerist's favorite, sodium! Maybe that's what makes up the "chicken stock"?  One good thing is that the chemical formula displayed for coffee is actually caffeine and the one displayed for cocoa is theobromine, so at least that makes a tiny bit of sense and they got water's formula and sodium correct too. 

People, I hate these TV shows...

Analogue or not an analogue: that is the question!

A beginning dialogue on this subject...this will set the stage for further discussions.

The Analogue Enforcement Act (AEA) was added to the Controlled Substances Act (CSA) of 1970 in 1986. It defines the term “controlled substance analogue” as a substance which:

1.   The chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II; AND

2.   Which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the nervous system of a controlled substance in schedule I or II; OR

3.   With respect to a particular person, which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II.

It is noted that the AEA only applies to a substance if it is intended for human consumption.

The AEA was essentially established to allow the Drug Enforcement Administration (DEA) to criminally prosecute cases involving so-called derivatives or “analogues” even though the specific substances are not explicitly scheduled under the CSA.  It is a way to control the tweaks and minor changes made by manufacturers of so-called “designer drugs” to circumvent the CSA and stay within the confines of the law or stay “legal”.  It is like the DEA's safety net that they can throw out and ensnare any rogue substances that are not scheduled. But this is not a black/white situation – it is more of a “gray area” as the use of the term “substantially similar” is very vague, obviously open for interpretation, and very, very, very unscientific.

There are various organizations/committees that are discussing this topic at length. One of these committees is the Advisory Committee for the Evaluation of Controlled Substance Analogs (ACECSA). Their website is http://www.druganalogs.org. This group primarily consists of forensic and academic chemists, toxicologists, pharmacologists and other scientists. Another committee is the Scientific Working Group for the Analysis of Seized Drugs.  Their website is http://www.swgdrug.org. This group primarily consists of federal, state, military, and even international chemists.  The DEA maintains a heavy presence on this committee.

Currently, cases involving the determination of a controlled substance analogue involve dueling chemists, toxicologists and pharmacologist as there is no consensus in the scientific community regarding what exactly is a controlled substance analogue.  Typically, the prosecuting attorneys will have consultation and testimony from the DEA chemists or toxicologists/pharmacologists while the defense will have consultation and testimony from chemists and toxicologists/pharmacologists from other entities.  The decision boils down to opinion vs. opinion.

There have been a couple of landmark cases regarding the AEA.  The first was a district court case in Colorado (USA vs. Damon S. Forbes et al. in 1992) that involved the determination of alphaethyltryptamine (AET) as an analogue of controlled substances, dimethyltryptamine (DMT) and diethyltryptamine (DET).  Ultimately it was determined that AET is not an analogue of DMT or DET as AET is a primary amine while DMT/DET are tertiary amines AND AET cannot be synthesized from DMT/DET AND the pharmacological effects of AET are not similar enough to DMT/DET.  The court also ruled that the definition of ‘substantially similar’ in the AEA was “void for vagueness” and therefore unconstitutional. 

The second case was heard by the US 8^th judicial circuit court of appeals (USA vs. Washam in 2002) and involved the determination of 1,4-butanediol as an analogue of gamma-hydroxybutyrate (GHB).  In the end, it was ruled that 1,4-butanediol was substantially similar to GHB because they were “both linear compounds containing four carbons and that there is only  difference between the substances on one side of their molecules” AND 1,4-butanediol is biotransformed in the human body to GHB, therefore if ingested, it would produce substantially the same pharmacological effects.

So, let us consider the substances Pyrovalerone, MDPV, and Alpha-PVP.

Pyrovalerone is a psychoactive substance that has been shown to be a norepinephrine and dopamine reuptake inhibitor, also known as an NDRI.  Pyrovalerone and other related pyrrolidino ketone compounds were patented in the United States on April 18, 1967.  It is a schedule V substance according to the CSA of 1970 and has been prescribed for the treatment of chronic fatigue or lethargy and as an anorectic drug for weight loss (even though it is rarely prescribed in the USA). Its IUPAC (International Union of Pure and Applied Chemistry) name is 1-(4-methylphenyl)-2-(1-pyrrolidinyl)-1-pentanone. Its molecular formula is C₁₆H₂₃NO and it has a molecular weight equal to 245.3 g/mol. Synonyms for pyrovalerone are Centroton, Thymergix, Valerophenone, and O-2371.

MDPV is a psychoactive substance that has been shown to be a norepinephrine and dopamine transporter inhibitor.  MDPV is an acronym for the name 3,4-methylenedioxypyrovalerone.  MDPV and other related methylendioxyphenylpyrrolidino-alkanones were patented in the United States on November 11, 1969.  It is a schedule I substance according to the CSA of 1970 and has no medical record of use in the United States.  Its IUPAC name is 1-(1,3-benzodioxol-5-yl)-2-(1-pyrrolidinyl)-1-pentanone. Its molecular formula is C₁₆H₂₁NO₃ and it has a molecular weight equal to 275.3 g/mol.  This compound was among the first substances detected in so-called “bath salts” products that were (and still are) available for sale over the Internet and in smokeshopes, headshops, and convenience stores.

Alpha-PVP is a substance that has an unknown mechanism of action and pharmacological effects. No published data is available regarding direct evidence of its pharmacology.  Its metabolism and excretion patterns in rat urine have been studied. Alpha-PVP was included in the document in which pyrovalerone and other related pyrrolidino ketone compounds were patented on April 18, 1967.  It is currently unscheduled in the United States’ CSA of 1970.  Its IUPAC name is 2-(1-pyrrolidinyl)-1-pentanone.  Its molecular formula is C₁₅H₂₁NO and it has a molecular weight equal to 231.3 g/mol.  Synonyms for alpha-PVP are alpha-pyrrolidinopentiophenone, α-PVP, PVP, O-2387, and Desmethylpyrovalerone.  After MDPV became emergency scheduled by the Federal government, this compound was used as a replacement substance and became very prevalent in the USA in “bath salt” products.

The chemical structures of these substances are:

Chemical structures of 3 related compounds

The DEA maintains that Alpha-PVP is a controlled substance analogue of MDPV.  There are cases still in litigation resulting from Operation Log Jam (July 2012) specifically about Alpha-PVP as an analogue. I have spoken to several (too many too count) scientists who think otherwise, but again, this just shows that opinions vary.

We won’t discuss these substances right now, but Operation Log Jam also included cases of the synthetic cannabinoids UR-144 and XLR-11.  The DEA maintains that UR-144 and XLR-11 are controlled substance analogues of JWH-018.

So, as a scientist, how would you determine what “substantially similar” means?

Should one consider 2D chemical structure or 3D chemical structure or both? What about shared functional groups? How much of a difference is significant? Methyl or ethyl group?  Is a compound containing a naphthoyl group substantially different from one that contains a tetramethylcyclopropyl group (as in the case of JWH-018 vs. UR-144)?  Is an exotic moiety like a methylenedioxyl group too significant of a difference (as in the case of MDPV vs. Alpha-PVP)? At what point is a change “too much” to be considered “similar”? Does synthetic pathway matter?  Do patents matter?

Is the use of structure activity relationships (SAR) valid when determining “substantially similar” pharmacological effects? Or should one rely solely on in vivo or in vitro data? Animal models?

Is it even possible to do this?  Is this type of legislation flawed?

All of these questions need answers but finding those answers will be a long journey.

Any thoughts on this one?

 

References

1.       Controlled Substances Act of 1970

2.      Controlled Substance Analogue Enforcement Act of 1986

3.      C Heron, J Costentin, J Bonnet.  Evidence that pure uptake inhibitors including cocaine interact slowly with the dopamine neuronal carrier.  Eur J Pharmacol. 264: 391-398 (1994).

4.      PC Meltzer, D Butler, JR Deschamps et al.  1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogs.  A promising class of monoamine uptake inhibitors.  J Med Chem. 49 (4) 1420-1432 (2006).

5.      LD Simmler, TA Buser, M Donzelli et al.  Pharmacological characterization of designer cathinones in vitro.  British Journal of Pharmacology. 168 (2) 458-470 (2013).

6.      US Patent 3,314,970 – α-pyrrolidino ketones (1967).

7.      JL Antonowicz, AK Metzger, SL Ramanujam.  Paranoid psychosis induced by consumption of methylenedioxypyrovalerone: two cases.  Gen Hosp. Psychiat.  33:  640e5-640e6 (2011).

8.     BL Murray, CM Murphy, MC Beuhler.  Death following recreational use of designer drug “bath salts” containing 3,4-methylenedioxypyrovalerone (MDPV).  J Med Tox.  8:  69-75 (2012).

9.      TM Penders and R Gestring.  Hallucinatory delirium following use of MDPV: “bath salts”.  Gen Hosp Psychiat.  33:  525-526 (2011).

10.  JW Spencer, C Long, AJ Scalzo et al.  Acute psychiatric, cardiopulmonary, and neurologic effects of laboratory-confirmed use of methylenedioxypyrovalerone (MDPV) “bath salts”.  Clin Tox.  49:  526-527 (2011).

11.   US Patent 3,478,050 – 1-(3’,4’-methylenedioxy-phenyl)-2-pyrrolidino-alkanones (1969).

12.  HH Mauer, C Sauer, FT Peter et al.  New designer drug α-pyrrolidinovalerophenone (PVP):  studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.  J Mass Spectrom.  44: 952-964 (2009).

13.  USA v. Damon S. Forbes et al. (1992) 806 F. Supp. 232.

14.  USA vs. Washam (2002) 312 F.3d 926,930.

15.   Alpha-Pyrrolidinovalerophenone (α-PVP) Analogue Status.  December 2011, Drug Enforcement Administration, Drug and Chemical Evaluation Section.  1-7