Synthetic cannabinoid

Synthetic cannabinoids are synthetic analogs of natural cannabinoids. They are used in cannabinoid research, as medicines and in designer drugs (such as synthetic cannabis).

History

The first synthetic cannabinoids were synthesized by Roger Adams in the early 1940s. Early cannabinoid research concentrated on THC as the main psychoactive and analgesic compound in cannabis. Non-psychoactive cannabinoids such as CBD are less well studied, besides being legal in many jurisdictions. Most synthetic cannabinoids are analogs of THC.

The first generation of THC analogs (synhexyl, nabilone, nabitan, nantradol) featured slight variations of the THC molecule, such as esterifying the phenolic hydroxy group, extending and branching of the pentyl side chain, or substituting nitrogen for oxygen in the benzopyran ring.[1] These analogs can be grouped into classical (HU-210), bicyclic (CP-55,940), and tricyclic (CP-55,244). Tritium-labelled cannabinoids such as [³H]CP-55,940 were instrumental in discovering the cannabinoid receptors in the early 1990s.[2]

Nabilone entered the clinic in 1981 as an antiemetic. Synthetic THC (marinol, dronabinol) entered the clinic in 1985 as an antiemetic and again in 1991 as an appetite stimulant.[3]

The second generation of THC analogs features compounds derived from anandamide (metanandamide), aminoalkylindole (WIN 55,212-2), pyrrole, pyrazole (SR-141716A), and indene (BAY 38-7271).

Specific cannabinoid receptor agonists
  CB₁ CB₂
Agonist Noladin ether HU-308, JWH-133
Antagonist SR-141716A, LY-320135, AM-281, AM-251 SR-144528, AM-630

HU-210 is apparently the most active cannabinoid used at present. It is up to 800 times more active than THC in mice. AM-404 (a paracetamol metabolite) is an inhibitor of endocannabinoid cellular uptake, prolonging their effects.[4] Nabitan, O-1057 and TMA are water-soluble.

Safety

Although most synthetic cannabinoids exhibit only the typical cannabinoid effects when used at appropriate doses, they are potent drugs capable of causing clinical intoxication and death (probably due to CNS depression and hypothermia) when used inappropriately. Many compounds have been banned in the U.S. and numerous other countries, although loopholes remain and new examples continue to be encountered on a regular basis.[5][6]

Detection in biological fluids

Serum concentrations of the synthetic cannabinoids are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolites, in most cases formed by oxidation of the alkyl side-chain to an alcohol and carboxylic acid followed by glucuronide conjugation, but also by N-dealkylation and aromatic hydroxylation, are usually present in urine at similar concentrations. The presence of synthetic cannabinoids or their metabolites in biofluids may be determined using immunoassay screening methods, while liquid chromatography-mass spectrometry is most often used for confirmation and quantitation.[7][8][9][10]

THC analogs

CBD analogs

See also

References

  1. ↑ Rao S. Rapaka; Alexandros Makriyannis, eds. (1987), Structure-Activity Relationships of the Cannabinoids (PDF), NIDA Research Monograph 79, U.S. Department of Health and Human Services
  2. ↑ Roger Pertwee (2006), "Cannabinoid pharmacology: the first 66 years", British Journal of Pharmacology 147: 163–171, doi:10.1038/sj.bjp.0706406, PMC 1760722, PMID 16402100
  3. ↑ Stefania Crowther; Lois Reynolds; Tilli Tansey, eds. (2010), The Medicalization of Cannabis (PDF), Wellcome Witnesses to Twentieth Century Medicine 40, Wellcome Trust Centre for the History of Medicine at UCL
  4. ↑ Raphael Mechoulam; Lumir Hanuš (2004), "The cannabinoid system: from the point of view of a chemist", in David Castle; Robin Murray, Marijuana and Madness: Psychiatry and Neurobiology, Cambridge University Press, pp. 1–18
  5. ↑ Trecki J, Gerona RR, Schwartz MD. Synthetic cannabinoid-related illnesses and deaths. N. Engl. J. Med. 373: 103-107, 2015.
  6. ↑ Mills B, Yepes A, Nugent K. Synthetic cannabinoids. Am. J. Med. Sci. 350: 59-62, 2015.
  7. ↑ Spinelli E, Barnes AJ, Young S et al. Performance characteristics of an ELISA screening assay for urinary synthetic cannabinoids. Drug Test. Anal. 7: 467-474, 2015.
  8. ↑ Huppertz LM, Kneisel S, Auwärter V, Kempf J. A comprehensive library-based, automated screening procedure for 46 synthetic cannabinoids in serum employing liquid chromatography-quadrupole ion trap mass spectrometry with high-temperature electrospray ionization. J. Mass Spectrom. 49: 117-127, 2014.
  9. ↑ Scheidweiler KB, Jarvis MJ, Huestis MA. Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography-high-resolution tandem mass spectrometry. Anal. Bioanal. Chem. 407: 883-897, 2015.
  10. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 10th edition, Biomedical Publications, Seal Beach, CA, 2014, p. 1863.


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