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Russian Chemical Bulletin, International Edition, Vol. 64, No. 6, pp. 1249—1266, June, 2015 1249
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1249—1266, June, 2015.
10665285/15/64061249 © 2015 Springer Science+Business Media, Inc.
Cannabinoids: structures, effects, and classification
V. A. Shevyrin and Yu. Yu. Morzherin
Ural Federal University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Email: vadim.shevyrin@gmail.com, yu.yu.morzherin@urfu.ru
The data on the chemical structures, biological effects, and use of cannabinoids on the
illegal market of new psychoactive substances were generalized. An extended classification
comprising new classes, groups, and subgroups of cannabinoids was proposed for better repre
sentation of their structural variety. The emergence of new synthetic cannabinoids which
belong to the groups of cycloalkanecarbonylindoles, indole and indazole3carboxamides,
and indole and indazole3carboxylates is closely associated with the market of new psycho
active substances.
Key words: biological activity, designer drugs, cannabinoids, cannabimimetics, cannab
inoid receptors.
Introduction
At present, synthetic cannabinoids are widely sold on
the illegal market of psychoactive drugs. A serious threat
to human society is that they are drugs of abuse adminis
tered to achieve euphoria. Many synthetic cannabinoids
like marijuana and marijuanaderived preparations con
taining the natural cannabinoid tetrahydrocannabinol have
changed, in a historically short period of time, from ob
jects of scientific investigations and pharmacological tests
to narcotic drugs prohibited by law in many countries.
Nevertheless, the illegal drug trade makes serious efforts
in searching for new types of psychoactive drugs, often
consulting the scientific pharmacological literature, and
offer synthetic modifications of the prohibited drugs to
users in order to circumvent the prohibitive measures.
Synthetic cannabinoids of new types constantly emerge
among users of psychoactive drugs in Russia. Structurally,
some of them are related to the already prohibited can
nabimimetics that come into widespread use in 2009. For
this reason, the structural identification of new psycho
active substances (NPS) emerging into the illicit traffic
and the development of reliable procedures for this pur
pose are pressing problems in the qualitative analysis of
narcotic drugs.
Cannabinoids, biological activity,
and the endocannabinoid system
Cannabinoids are a group of at least 66 biologically
active terpenophenols derived from 2substituted 5amyl
resorcinol, which are found in cannabis (Cannabis sati
va)1,2 and cannabis products (e.g., marijuana and hash
ish3), as well as their synthetic analogs capable of binding
to cannabinoid receptors.4
The biological activity of cannabis and cannabis prod
ucts have long attracted the attention of both oriental and
European doctors. Cannabis was traditionally used as
a remedy for its analgesic, tonic, antispasmodic, and anti
emetic effects.5 The earliest mention of the medicinal
properties of cannabis dates back to 2700 B.C. when Chi
nese doctors used it to treat malaria, rheumatic pain, and
some other diseases as well as for anesthetic purposes.6 In
European medicine, cannabis came into wide use in the
midXIX century: having examined the Indian experience,
British doctors began to actively employ cannabis as an
analgesic, an appetiteincreasing means, an antiemetic,
and antispasmodic and antiinflammatory agent. In the
latter half of the XIX century, over 100 studies concerned
with the efficacy of cannabis against various diseases were
published, and cannabis products were retained in the
pharmacopeias of some countries for a long period of time.6
However, the medical interest in cannabis gradually de
clined. The reasons include (1) its unpredictable pharma
cological effect depending on the quality of crude can
nabis and the methods for the manufacture of its prepara
tions, (2) the synthesis of many drugs with welldefined
therapeutic effects, and (3) the psychoactive properties of
cannabis.7 That is why cannabis and cannabis products
were recognized as narcotic drugs and prohibited (initially
by some countries8 and ultimately by the United Nations
Single Convention on Narcotic Drugs9). In Russia, can
nabis and cannabis products were also made illegal. At
present, the medical use of cannabis products is seriously
limited because of their wellknown side effects.10
Shevyrin and Morzherin1250 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
Nabilone
An essential milestone in the understanding of what is
behind the psychoactive effect of cannabis was the deter
mination of the structures and pharmacological charac
teristics of its principles:6,11 9tetrahydrocannabinol (1)
(THC), its isomeric 8tetrahydrocannabinol (2), can
nabinol (3), and cannabidiol (4). Cannabinol, the first
natural cannabinoid isolated in the late XIX century, was
structurally identified in the 1930s; the total synthesis of
this compound was conducted in the 1940s.12,13 Using
improved methods for extracting the principles of can
nabis, Mechoulam et al. isolated cannabidiol and deter
mined its structure in 1963.14 A year later, pure THC was
isolated, structurally characterized, and successfully syn
thesized from cannabidiol15 as well as from simpler or
ganic matter.16
By nearly that time, THC was found to be the main
psychoactive constituent of cannabis; the psychoactive
potential of cannabinol is much weaker, while cannabidi
ol is absolutely inactive in this respect.11
The structural identification of the above natural can
nabinoids and the availability of their chemically pure sam
ples considerably spurred the investigations of the thera
peutic potential of these compounds in the 1970s, mainly
in Great Britain, the USA, and Canada, where the restric
tions on the medical use of their preparations were partial
ly lifted by the local legislative authorities.5,11 The best
results were achieved with dronabinol (a THC stereo
isomer) and nabilone (a synthetic THC analog) used as
antiemetics in cancer patients under chemotherapy. In
clinical trials, they were superior to the antiemetics
employed at that time.5,6,17 Those encouraging results
prompted the Ministry of Health of Canada to approve
the medical use of nabilone in 1982, regardless of its side
effects; dronabinol was allowed in the USA in 1985.
Much attention was also given to the use of cannab
inoids as analgesics. The results obtained were quite satis
factory, and the US pharmaceutical company Pfizer Inc.
began to develop synthetic THC analogs as potential an
algesics.11 In 1979, the Pfizer researchers synthesized
2[(1S,3R)3hydroxycyclohexyl]5(2methyloctan2
yl)phenol (CP 47497) and its homologs with different
lengths of the alkyl substituent (from dimethylhexyl to
dimethylnonyl).18,19 The testing of these compounds re
vealed desired high biological activity. However, their pro
nounced narcogenic potential (several times that of THC)
was immediately noticed as well.20 The more potent anal
gesic 2[(1R,2R,5R)5hydroxy2(3hydroxypropyl)
cyclohexyl]5(2methyloctan2yl)phenol (CP 55940)
obtained by the same company shortly after21 exhibits even
higher narcotic activity.
The key discovery made in 1988 extended the concept
of the impact of cannabinoids on the body and opened up
the way to the targeted synthesis and primary screening of
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1251
new compounds with desired biological activity. When
tritiumlabeled CP 55940 was injected into rats, this com
pound was found to specifically bind to certain molecular
structures of brain22 named cannabinoid CB1 receptors.6
In 1990, the results of molecular cloning of this receptor
were published.23 The receptor of second type, CB2, was
identified in 1993.6,24
The discovery of cannabinoid receptors prompted
searching for endogenous ligands that can bind to these
receptors. Main endogenous ligands (endocannabinoids)
were found in 1992—199525—27 and include arachidonic
acid derivatives: N(2hydroxyethyl)arachidonamide (an
andamide) (5) and 2Oarachidonylglycerol (6). Later,
some other endocannabinoids were discovered. Structur
ally, they are saturated or unsaturated acid amides (e.g.,
oleamide).28 The physiological properties of endocannab
inoids are much the same as those of natural and synthetic
exogenous cannabinoids.
The discovery of endocannabinoids was followed by
description of their metabolism (biochemical synthesis,
release, transportation, and degradation), which gave
an idea of a new signaling system named endocannab
inoid system. By convention, the endocannabinoid sys
tem includes cannabinoid receptors, their endogenous
ligands, and physiological mechanisms of interaction be
tween them.11
Data were required to elucidate the role of the target
cannabinoid receptors in the regulation of the body´s func
tions and physiological processes they trigger, including
those initiated by exogenous ligands. These processes are
directly related to the pharmacological activity of cannab
inoids, which can be predicted in terms of the affinity of
cannabinoids for the one or other type of receptors.11 The
highest concentration of CB1 receptors is found in the
central nervous system, including the brain cortex. They
are also located in the peripheral nervous system, hypo
physis, adrenals, reproductive organs, heart, lungs, and
gastrointestinal tract. The uneven distribution of CB1
receptors in the central nervous system may account, to
some extent, for the psychoactive effects of cannabinoids.29
Numerous data provide evidence for a direct relationship
between the affinity of cannabinoids for CB1 receptors
and their narcogenic potential.30—33 Cannabinoid CB2 re
ceptors are mainly located on the surface of the cells of the
immune system, mediate many physiological processes
involving immune responses, and influence the body´s
resistance to infectious, allergic, and oncological di
seases.29,34
The serious interest in cannabinoids was revived by the
advance in the understanding of their mechanisms of ac
tion. The synthesis of new cannabinoids was intended to
obtain compounds that would be specific for the one or
other type of cannabinoid receptors or would simulta
neously affect both with different competitive abilities.
The tendency to interact with receptors in the one or other
way can, in turn, predetermine the pharmacological ac
tivity of a new cannabinoid.11
(6aR,10aR)9Hydroxymethyl6,6dimethyl3(2me
thyloctan2yl)6a,7,10,10atetrahydro6Hbenzo[c]
chromen1ol obtained in 1988 was among the first pre
sumptive drugs containing synthetic cannabinoids; this
THC analog was named HU210.35 Preliminary tests of
HU210 revealed its high analgesic activity. However, the
medical use of this compound was precluded because of its
considerable narcogenic potential (more than 100 times
that of THC), regardless of some positive aspects.36—39 Its
stereoisomer HU211 obtained at the same time is also an
analgesic but incapable of binding to cannabinoid recep
tors and thus showing no psychoactive properties. This
compound is currently under extensive medical examina
tion for the treatment of, e.g., craniocerebral traumas.40
In 1991, (R)(+)[2,3dihydro5methyl3(4mor
pholinylmethyl)pyrrolo[1,2,3de]1,4benzoxazin6yl]
(naphthalen1yl)methanone (WIN552122) was synthe
sized41 when trying to obtain analogs of the antiinflam
matory drug pravadoline and purposefully searching for
a structure—antiinflammatory activity relationship. This
compound was found to show affinity for cannabinoid
receptors42 and was the first representative of a class of
aminoalkylindoles that include a large number of more
recent synthetic cannabinoids. Nowadays, despite some
of its valuable pharmacological features, WIN552122 is
Shevyrin and Morzherin1252 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
used as a pharmacological probe for cannabinoid recep
tors, finding no therapeutic applications because of its
narcogenic activity.
All the aforementioned compounds can bind more or
less equally to cannabinoid receptors of both types. Later,
compounds capable of selectively binding to the one or
other type of receptors were obtained. The first highly
selective antagonist at CB1 receptors was reported in 1994.
This 1,5diarylpyrazole derivative, namely, Npiperidino
5(4chlorophenyl)1(2,4dichlorophenyl)4methyl
1Hpyrazole3carboxamide (SR141716A, Rimonabant),43
is 1000 times more selective to CB1 receptors than to CB2
ones. Being a CB1 receptor antagonist, SR141716A can
block the impact of psychoactive cannabinoids, so narco
genic effects are mostly associated with receptors of the
first type.44 In 2006, Rimonabant was approved as a drug
in Europe to control obesity. Clinical trials of Rimona
bant for the treatment of obesity were also conducted in
Russia.34 However, this drug was withdrawn from the mar
ket in 2008 for its side effects related to mental disorders.
Nevertheless, Rimonabant is still considered the most
promising drug for the therapy of obesity. Researchers all
over the world are interested in the development of potent
and selective CB1 receptor antagonists that would have
the best pharmacokinetic profile and therapeutic index.
Many Rimonabant analogs have been synthesized to date;
they vary in both the substituents to the pyrazole ring and
the heterocycle itself (pyrrole, imidazole, triazole, pyr
azoline, pyridine, etc. instead of pyrazole).45
The first highly selective inverse agonist at CB2 recep
tors (N[(1S,2S,4R)1,3,3trimethylbicyclo[2.2.1]heptan
2yl]5(4chloro3methylphenyl)4methyl1(4meth
ylphenyl)1Hpyrazole3carboxamide, SR144528) was
synthesized in 1998.46 Like SR141716A, this compound
serves as a good tool for investigations of cannabinoids.47
During the targeted development of synthetic analogs
of THC that would have its pharmaceutical properties but
would be deprived of high narcogenic potential, (1R,2R,5R)
2[2,6dimethoxy4(2methyloctan2yl)phenyl]4hy
droxymethyl7,7dimethylbicyclo[3.1.1]hept3ene
(HU308) was obtained as an experimental compound.48
HU308 is a selective CB2 receptor agonist. This com
pound synthesized not so much for further medical appli
cations as for investigations of the structure—activity rela
tionship in cannabinoids proved to be of therapeutic inter
est, for instance, as an analgesic.49 The therapeutic poten
tial of HU308 is still under examination.
Newer synthetic cannabinoids were obtained when
searching for ways through which the different units of the
endocannabinoid system can be affected as well as for
a relationship between chemical structure and pharmaco
logical activity. An essential numerical characteristic of
the biological activity of synthetic cannabinoids, which is
cited in the contemporary pharmacological literature and
employed for estimation of the above relationship, is ex
perimental affinity for cannabinoid receptors; there are
serious correlations between affinity and biological acti
vity, including narcogenic potential.50 This allows prel
iminary screening of cannabinoids for pharmacological
activity.
Animal tests and some clinical trials revealed that CB1
receptor antagonists are efficient as anorectics and drugs
for the treatment of schizophrenia and cognitive and mem
ory disorders in some neurodegenerative (Alzheimer´s etc.)
diseases. Apart from appetiteincreasing and antiemetic
activity, CB1 receptor agonists show neuroprotective prop
erties. They are effective when treating motor disorders
caused by multiple sclerosis and spinal cord traumas. These
agonists exhibit pronounced analgesic activity, are used to
treat glaucoma, and have antitumor and cardioprotective
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1253
properties.6,11,29,38,51 Future studies should be focused on
separation of the therapeutic and side (first of all, psycho
active) effects of CB1 receptor agonists.
Cannabinoid CB2 receptor agonists showing antiin
flammatory and immunosuppressive activity are also of
great interest.29,34 For the study of the therapeutic value of
CB2 receptors, it was necessary to synthesize compounds
with high affinity for receptors of this type and with low
(or no) affinity for CB1 receptors; this is a challenging task
in modern pharmacology. It was postulated that CB2sel
ective agonists could be useful for the treatment of inflam
matory and some other diseases, exhibiting an anesthetic
(but no unwanted psychoactive) effect. Based on this pos
tulate, research laboratories and pharmaceutical compa
nies still make considerable efforts in searching for CB2
selective agonists and synthesize a broad spectrum of struc
turally various compounds.52—61
Synthetic cannabinoids as drugs of abuse
Starting in 2004, various herbal smoking blends ("Spice
silver", "Spice gold", "Spice diamond", "Smoke", "Smoke
Plus", "Sence", "Skunk", "Yucatan Fire", etc.62) were sold,
mostly via online shopping, in Switzerland, Austria, Ger
many, and other European countries. Further active dis
tribution of such herbal smoking and incense blends over
Europe, North America, and New Zealand in 2004—2008,
as well as somewhat later over Russia, revived the fashion
(first of all, among young people) for psychoactive drugs;
they are commonly named "Spice" after the correspond
ing popular brand name. Instrumental in this "revival" was
the aggressive advertising policy by Internet shops, which
sold "Spice" products as merely relaxing herbal blends,
thereby concealing their true composition.
Originally, manufacturers promoted their Spice prod
ucts as blends of traditional legal exotic and medicinal
herbs composed to imitate the psychoactive effect of mar
ijuana. In Internet forums, users described strong hash
ishlike effects after smoking these types of herbal blends.
Being advertised and easily accessible for a number of
years, Spice products were recognized by users of these
new experimental preparations as well as by many hashish
and marijuana users who wanted for legal alternatives to
these narcotic drugs.63,64 Even though Spice products were
more expensive than illicit marijuana sold on the black
market, their legality and negative drug test results made
Spice products very popular.
The Spice boom reached a peak in mid2008 and
caused a broad public response, notably in Germany, for
their enormous popularity. First of all, this was a response
to a number of accidents and mental disorders in Spice
users.65 Toxicologists noticed that the behavior of their
patients is typical of marijuana users. The symptoms in
clude red eyes, tachycardia, anxiety, paranoia, and hallu
cinations accompanied by transient global amnesia, lack
of the time sense,66 and distinct Spice addiction (with
a withdrawal syndrome). However, toxicological tests de
tected no tetrahydrocannabinol.
Initial attempts to explain why Spice products have
the narcogenic effect on the body failed because it was the
herbal composition claimed by manufacturers that was
under examination first and foremost. However, it gradu
ally became clear that those exotic herbs could hardly
produce such a strong psychoactive effect.64 Although
a suspicion arose that Spice products could contain syn
thetic compounds, the lack of analytical data precluded
their identification at the laboratories of the Ministry of
Health of Germany as long as several months.
In December 2008, the pharmaceutical company
"THC Pharm" (Frankfurt, Germany) specializing in the
synthesis and study of cannabinoids published its account
of the compositions of several Spice brands.67 All of them
were found to contain the synthetic cannabinoid JWH018
in different concentrations. Soon after, two research teams
at the Freiburg University (Freiburg, Germany)62 and the
National Scientific Institute of Health (Japan)68 simulta
neously identified in some Spice products the C8 homolog
of the synthetic cannabinoid CP 47497 (CP 47497C8)
with its transdiastereomer as a byproduct. Some smok
ing blends contain both CP 47497C8 and JWH018.
The consequence was that the identified synthetic can
nabinoids JWH018 and CP 47497C8 along with their
most closely related homologs were made illegal by the
German controlling bodies63 on January 22, 2009 and,
almost immediately, by some other European countries.64
However, contrary to the expectations, that decision did
not solve the Spice problem, producing quite the reverse
effect in many respects because of imperfect legislation.
Having realized during the preceding years the possibility
of unpunishable enrichment and formed a certain social
stratum of users, the illegal drug trade turned every legisla
Shevyrin and Morzherin1254 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
tive lacuna to its advantage and marketed new kinds of
synthetic cannabinoids similar to the already prohibited
ones in both chemical structure and psychoactive effect.
This activity has become quite deliberate in the last few
years, involving the published data on the synthesis and
medical tests of synthetic cannabinoids.
For instance, the new synthetic cannabinoid JWH073,
which is a butyl homolog of JWH018 and is formally not
banned, was identified in Spice products as early as March
2009.63 Data for its GCMS detection were presented for
the first time. The synthetic cannabinoid HU210 was
reported that year to be found in smoking blends in the
USA.69 In late 2009, two more synthetic cannabinoids of
the "second wave", JWH250 and JWH398,64,70,71 were
identified by mass spectrometry in Europe.
In contrast to the European countries, in which the
distribution of synthetic cannabinoids was made illegal
almost immediately upon the official accounts of their
identification, no mechanism was developed in Russia in
2009 to oppose the imminent enormous threat of NPS
distribution among people. The global distribution of syn
thetic cannabinoids was not stopped because of the lack of
relevant normative documents and provision of expert
groups with analytical techniques and scientific informa
tion regarding identification of these compounds. The his
tory of Spice distribution in Russia followed in many re
spects the negative foreign experience. Clearly, the lack of
the analytical characteristics and techniques for identifi
cation of synthetic cannabinoids diverted all Russian con
trolling bodies onto the wrong path pursued for a long
period of time.72 For instance, based on Internetwide
information, they limited in Russia the distribution of
Hawaiian rose, sage of the diviners (Salvia divinorum),
and blue lotus all allegedly found in smoking blends and
responsible for their narcotic activity. Only after legisla
tive limitations for these plants had been adopted, proce
dures for their identification were developed, but none of
these plants were detected in smoking blends. The true
origin of their psychoactive effect remained unclear until
first publications concerning the detection, methods of
identification, and analytical characteristics of some syn
thetic cannabinoids appeared in foreign scientific litera
ture.62—66 As in other countries, the development of nor
mative documentation for the control of synthetic can
nabinoids was substantially accelerated by mass media
publications (November—December 2009) regarding nu
merous injuries and fatal accidents caused by mental dis
orders in people smoking such blends. The Russian Gov
ernment Resolution No. 1186 (December 31, 2009) in
cluded a number of synthetic cannabinoids (e.g., the
most commonly encountered JWH018, JWH073, and
CP 47497C8) in Schedule I of the narcotic drugs prohib
ited in Russia. Immediately after the publication of this
Resolution, the expert groups encountered the lack of an
alytical techniques and published data for identification of
synthetic cannabinoids. This problem became critical after
new types of such compounds had emerged into the illicit
traffic instead of the prohibited ones.73 Moreover, new
types of cannabinoids were often detected far in advance
of first papers concerning their analytical characteristics,
and an ever increasing number of new synthetic canna
binoids was constantly reported. Subsequently, it was not
uncommon that they emerged first in Russia and, in some
period of time, elsewhere in the world. This is due to the
great capacity of the Russian market as well as to the
organized groups of illicit traffickers skilfully taking ad
vantage of the defective drug legislation in use. Synthetic
cannabinoids structurally related to, but slightly modified
against, the prohibited ones could not be legally classified
as narcotic drugs. This legal problem was partially solved
by the Russian Government Resolutions No. 882 (Octo
ber 30, 2010) and No. 1178 (November 19, 2012), in which
the definition "drug derivative" was introduced and then
validated. This definition partly covers compounds struc
turally related to narcotic drugs but not included in Sched
ule I of Narcotic Drugs as individual items. Drug traffick
ers responded to this measure by offering new synthetic
cannabinoids manufactured through more profound struc
tural modification. Therefore, the identification of syn
thetic cannabinoids and the provision of experts with
a developed methodology including analytical techniques
and the characteristics of compounds still remain modern
challenges to drug analysts.
Classification of cannabinoids
Biologically, cannabinoids are chemical compounds
that can interact, in some or other way, with cannabinoid
receptors. Such compounds can be divided into can
nabimimetics (they exhibit cannabinoid activity and are
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1255
mostly CB1 receptor agonists) and antagonists capable of
binding to cannabinoid receptors (they produce no can
nabinoid effects, simply blocking these receptors for other
substances).4,50
The term "cannabinoids" covers compounds having di
verse chemical structures underlying the following con
ventional classification.4,50,74
1. Classical cannabinoids: dibenzopyran derivatives
(THC, its isomers, and structurally related synthetic ana
logs such as, e.g., HU210).
2. Nonclassical cannabinoids: synthetic cyclohexyl
phenol derivatives (3arylcyclohexanols such as, e.g., CP
47497 and CP 55940).
3. Hybrid cannabinoids combining the structural fea
tures of classical and nonclassical cannabinoids.
4. Aminoalkylindoles: a large class of synthetic can
nabinoids subdivided, according to the current classifica
tion, into naphthoylindoles, phenylacetylindoles, benzo
ylindoles, and naphthylmethylindoles. It was the first three
groups of compounds that were used by criminal business
as designer drugs giving birth to the era of smoking blends.
5. Eicosanoids: endocannabinoids (such as, e.g., anand
amide) or their synthetic analogs.
6. Others: such compounds as diarylpyrazoles (e.g.,
SR141716A and SR144528), naphthoylpyrroles, naph
thylmethylindenes, and other cannabinoids constituting
no classes in their own right.
The above classification cannot be considered exhaus
tive, especially for aminoalkylindoles. A first extension75
to this classification was made only in mid2013 by intro
ducing such groups as adamantoylindoles (or, more cor
rectly, adamantanecarbonylindoles), cyclopropanoylin
doles (cyclopropanecarbonylindoles), indolecarboxamides
(indole3carboxamides), and indazolecarboxamides
(indazole3carboxamides) widely distributed as NPS
since 2011.
Despite this attempt,75 the classification is still defec
tive because a number of new compounds as well as the
potential structural variety of substituents within certain
groups are ignored.
First of all, it should be noted that the class name
"aminoalkylindoles" originating from compounds like
WIN552122 has lost much of its initial sense because of
successful replacement of the aminoalkyl group in posi
tion 1 of the indole ring by alkyl or aryl groups without
losing the cannabinoid activity. This class of compounds
mainly consists of 3acylindole derivatives subdivided into
groups according to the acyl substituent structure. There
fore, the only common structural moiety found in most of
the compounds of this class is indole3carbonyl, and
a new, more accurate name "3carbonylindoles" can be
proposed for them. Naphthylmethylindoles should be
placed in a new small class of "miscellaneous cannab
inoids" (the former class name "other cannabinoids"). It is
expedient to unite synthetic cannabinoids containing the
indol3yl cycloalkyl ketone moiety into a new large group
of cycloalkanecarbonylindoles within 3carbonylindoles.
Cycloalkanecarbonylindoles can be further subdivided, de
pending on the cycloalkane structure, into smaller groups
such as, e.g., adamantanecarbonylindoles and cyclo
propanecarbonylindoles.
Along with indole3carboxamides, a new group of syn
thetic cannabinoids based on indole3carboxylates should
also be referred to as 3carbonylindoles. This group will
include indole3carboxylic acid esters identified in smok
ing blends in 2012—2014.
Because the modification of synthetic cannabinoids,
for the synthesis of NPS as well, often involves replace
ment of the indole heterocyclic system by the indazole
one, an increasing number of new synthetic cannabinoids
contain the indazole3carbonyl moiety. The substituents
in positions 1 and 3 of the indazole ring are the same as
in 3carbonylindoles. For instance, 3naphthoylind
azoles,76—78 indazole3carboxamides,79—82 and indazole
3carboxylates83 have been identified as designer drugs to
date. Therefore, 3carbonylindazoles can be regarded as
a new class subdivided into much the same groups as those
for 3carbonylindoles.
Based on the above reasoning, the current classifica
tion of cannabinoids should be recast as follows:
1. Classical cannabinoids.
2. Nonclassical cannabinoids.
3. Hybrid cannabinoids.
4. 3Carbonylindoles:
4.1. Naphthoylindoles;
4.2. Phenylacetylindoles;
4.3. Benzoylindoles;
4.4. Cycloalkanecarbonylindoles:
4.4.1. Adamantanecarbonylindoles;
4.4.2. Cyclopropanecarbonylindoles;
4.5. Indole3carboxamides;
4.6. Indole3carboxylates;
4.7. Other 3carbonylindoles.
5. 3Carbonylindazoles:
5.1. Naphthoylindazoles;
5.2. Indazole3carboxamides;
5.3. Indazole3carboxylates.
6. Eicosanoids.
7. Miscellaneous cannabinoids:
7.1. Diarylpyrazoles;
7.2. 3Naphthoylpyrroles;
7.3. Naphthylmethylindoles;
7.4. 2Naphthoylbenzimidazoles;
7.5. Naphthylmethylindenes;
and other groups.
Of course, since new synthetic cannabinoids emerge
constantly, the classification proposed above cannot be
"fixed for ever" and should be permanently modified and
supplemented with new classes of compounds. Never
theless, this version of classification conforms better to
Shevyrin and Morzherin1256 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
a structural variety of synthetic cannabinoids, provides
their more detailed systematization, and allows elabora
tion of more definite legal measures against the distribu
tion of synthetic cannabinoids as designer drugs. Below
we will dwell on some groups of synthetic cannabinoids by
analyzing the literature data on their structures, the goals
of synthesis, and identification on the NPS market.
3Carbonylindoles
This class includes various 3acylindole derivatives
containing, e.g., oxo, ester, or carboxamide groups in po
sition 3 of the heterocycle.
Naphthoylindoles
These are 3naphthoylindole derivatives having the
general structural formula shown below.
The pioneering investigations aimed at the targeted
synthesis of a large group of cannabinoids representing
Nalkyl3naphthoylindoles and considered a point of de
parture for the development of the whole class of 3carbo
nylindoles were effected in the 1990s at the Clemson Uni
versity (USA).84 The investigations were supervised by
J. W. Huffman, after whom the series of such compounds
has been named JWH. All the synthesized "experimental"
compounds served to study a relationship between the
chemical structure of cannabinoids and their affinity for
CB1 and CB2 receptors as well as to gain insight into the
mechanisms by which cannabinoids interact with the
corresponding receptors. The synthetic cannabinoid
WIN552122 and THC were used as "parent" compounds
for structural modeling. Their structures were deliberately
simplified and combined using a computerassisted model
to reveal reactive sites in these molecules and obtain a new
hybrid structure.84 Several 3naphthoylindole derivatives
containing normal Nalkyl substituents (C3—C7) were
synthesized. Biological tests of these compounds con
firmed the hypothesis that a necessary and sufficient con
dition for the cannabinoid activity to appear is that the
indole ring should contain the naphthoyl or similar group
in position 3 and an Nalkyl substituent C4—C6 in place of
the aminoalkyl fragment of WIN552122. For instance,
the pronounced cannabinoid activity and affinity for both
types of receptors are exhibited by (2methyl1pentyl
1Hindol3yl)(1naphthyl)methanone (JWH007), one
of the first compounds of this series.
Later, Huffman et al. obtained a number of 3naph
thoylindoles containing various alkyl and aminoalkyl sub
stituents.85—88 Most of them show affinity for cannab
inoid receptors of both types. However, some prefer to
bind to CB1 receptors, while others, to CB2 ones.
The synthesized compounds with high affinity for both
types of receptors as well as with a pronounced narcogenic
potential include, apart from JWH007, (naphthalen1yl)
(1pentyl1Hindol3yl)methanone (JWH018), (1but
yl1Hindol3yl)(naphthalen1yl)methanone (JWH073),
(1hexyl1Hindol3yl)(naphthalen1yl)methanone
(JWH019), (4methylnaphthalen1yl)(1pentyl1Hin
dol3yl)methanone (JWH122), (4ethylnaphthalen1
yl)(1pentyl1Hindol3yl)methanone (JWH210),
(4methoxynaphthalen1yl)(1pentyl1Hindol3yl)
methanone (JWH081), (4methylnaphthalen1yl)[1
(2morpholin4ylethyl)1Hindol3yl]methanone
(JWH193), (4methoxynaphthalen1yl)(2methyl1
pentyl1Hindol3yl)methanone (JWH098), etc.
Almost simultaneously, the research team headed by
A. Makriyannis89 at the Connecticut State University
(USA) obtained a large series of compounds (convention
ally named AM) with the aim of studying their cannab
inoid activity. First representatives of this group included
3naphthoylindole derivatives in which an aminoalkyl
chain as a cyclic amine is attached to the indole N atom
through a carbon atom.90 An example is [1(1methyl
piperidin2ylmethyl)1Hindol3yl](naphthalen1yl)
methanone (AM1220). The 3naphthoylindole deriva
tives obtained later contain normal Nalkyl substituents
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1257
with a terminal halogen atom or some other terminal
groups.91,92 An example is [1(5fluoropentyl)1Hindol
3yl](naphthalen1yl)methanone (AM2201), an analog
of JWH018.
Phenylacetylindoles
First representatives of phenylacetylindoles, viz.,
Npentyl3phenylacetylindoles, were obtained at the next
step in the study of a structure—activity relationship,93
shortly after the synthesis of naphthoylindoles.
Generally, these compounds are not highly selective to
CB2 receptors. However, some of them show equally high
affinity for receptors of both types. These are 2(2me
thoxyphenyl)1(1pentyl1Hindol3yl)ethanone
(JWH250) and 2(2chlorophenyl)1(1pentyl1Hin
dol3yl)ethanone (JWH203). 2(2Methylphenyl)1(1
pentyl1Hindol3yl)ethanone (JWH251) binds to CB1
receptors more readily than to CB2 ones.93
Benzoylindoles
The formation and expansion of the 3benzoylindole
group is due to the studies aimed at modifying the antiin
flammatory drug pravadoline designed in the 1980s. This
drug has good anesthetic properties as well.41,42,94
A great stride in this direction was made by the re
search team at the Connecticut State University (USA).
Compounds of this group were investigated in parallel with
the synthesis and study of 3naphthoylindoles.90—92 One
of the first representatives is [6iodo2methyl1(2mor
pholin4ylethyl)1Hindol3yl](4methoxyphenyl)
methanone (AM630, or 6iodopravadoline). This potent
CB2 receptor antagonist shows weak affinity for CB1 re
ceptors.95 Many compounds were synthesized during the
structural modeling, including (2iodo5nitrophenyl)[1
(1methylpiperidin2ylmethyl)1Hindol3yl]meth
anone (AM1241). This strong and selective CB2 receptor
agonist possesses analgesic properties, with no pronounced
Shevyrin and Morzherin1258 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
side effects on the central nervous system.96,97 The other
synthesized compounds exhibiting very high affinity for
CB1 receptors and, consequently, having an narcogenic
potential include [1(5fluoropentyl)1Hindol3yl](2
iodophenyl)methanone (AM694)98 and (2iodophen
yl)[1(1methylpiperidin2ylmethyl)1Hindol3yl]
methanone (AM2233).99
Cycloalkanecarbonylindoles
Many relatively recent synthetic cannabinoids not in
cluded in the generally accepted classification are united
into a new group of cycloalkanecarbonylindoles. It is rea
sonable that this group should also comprise compounds
containing the indol3ylcycloalkylcarbonyl moiety.
Adamantanecarbonylindoles. This type of cannabinoids
include 3adamantoylindole derivatives with the general
structural formula shown in the right inset. These com
pounds can be classified as a subgroup of cycloalkane
carbonylindoles with adamantane as an cycloalkane.
(Adamantan1yl)[1(1methylpiperidin2ylmethyl)
1Hindol3yl]methanone (AM1248) seems to be a first
representative of this subgroup that was synthesized and
tested for cannabinoid activity.92,93 Several structurally
related compounds (AM1248 and AB001)100 highly se
lective to CB1 receptors were studied later.101,102
(2,2,3,3Tetramethylcyclopropanecarbonyl)indoles. This
subgroup includes 3(2,2,3,3tetramethylcyclopropane
carbonyl)indole derivatives synthesized at the Abbott
laboratory (USA) when searching for new CB2selective
cannabinoids.101,103—105
One of the compounds obtained, viz., [1(2morpho
lin4ylethyl)1Hindol3yl](2,2,3,3tetramethylcyclo
propyl)methanone (A796260), is a potent CB2selective
cannabinoid. In addition, its high therapeutic potential as
Pravadoline
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1259
an anesthetic is useful for further investigations of the CB2
receptor pharmacology.106
The other synthesized compounds are not highly selec
tive; some slightly prefer CB2 receptors but display con
siderable cannabinoid activity at receptors of both types.
A series of compounds of this subgroup107,108 that are
modified (1Hindol3yl)(2,2,3,3tetramethylcycloprop
yl)methanone were first identified as NPS in Russia in the
summer of 2011. It was also found that the strained cyclo
propane ring of these compounds undergoes thermal open
ing at T > 150 C to give stable acyclic isomers.
Indole3carboxamides
The presence of the carboxamide group in position 3 of
an azaheterocycle is no novelty in the modeling of syn
thetic cannabinoids (see, e.g., diarylpyrazoles SR141716A
and SR14452843,47); however, indole3carboxamides
have been synthesized only recently.109,110
Some of these compounds show very high affinity for
cannabinoid receptors of both types. Moreover, some
structures (CBM018, ACBM2201, MEPIRAPIM,
MMB2201, etc.)111 are water soluble, which is a new and
medically useful property.
Indole3carboxamides have been widely distribut
ed as NPS in the illegal drug market since 2012. Com
pounds containing Nnaphthyl, N1carbamoylalkyl, and
N1methoxycarbonylalkyl groups in the amide frag
ment79,80,82,112,113 as well as (4methylpiperazino)(1pen
tyl1Hindol3yl)methanone (MEPIRAPIM)92 have
since been identified in smoking blends.
Indole3carboxylates
A group of new compounds were identified as NPS on
the market of designer drugs between October 2012 and
the first half of 2014. Chemically, these are esters of in
dole3carboxylic acids (QCBL018, QCBL2201, and
QCBLCHM) structurally related to wellknown and pro
hibited synthetic cannabinoids.82,83
Shevyrin and Morzherin1260 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
Compounds of this group are widespread in the illicit
traffic; they are Nalkyl or Narylindole3carboxylic
acids esterified with 8hydroxyquinoline or 1naphthol.
Apparently, this novel type of synthetic cannabinoids was
designed by manufacturers of psychoactive substances
at their laboratories; data on the synthesis and biological
activity of the esters of indole3carboxylic acid with
8hydroxyquinoline or 1naphthol are still lacking in the
overt literature.
Other 3carbonylindoles
It should be noted that the class of 3carbonylindoles
(aminoalkylindoles) is being constantly augmented with
newly synthesized compounds, so new large groups of com
pounds will possibly be added to the classification.
Some new compounds can be tentatively united into
a group of "other 3carbonylindoles" within this class.
Specifically, this relates to an acyclic isomer of
TMCP018,107,108 produced by thermal rearrangement of
the cyclopropane ring.
3Carbonylindazoles
In March 2012, synthetic cannabinoids of a new type,
along with indole3carboxamides, emerged among users
of psychoactive drugs in Russia. These synthetic cannab
inoids are similar to the wellknown indole cannabimi
metics, except that their structure contains indazole as the
basic heterocycle. In 2013 and 2014, the market of NPS
was flooded with synthetic cannabinoids based on the in
dazol3ylcarbonyl system. Over that period, indazole3
carboxamides, indazole3carboxylates, and naphthoylin
dazoles were identified as NPS.
Nowadays, 3carbonylindazoles constitute a class in
its own right, with much the same subdivision as that for
3carbonylindoles.
Naphthoylindazoles
A first representative of synthetic 3naphthoylindazole
cannabinoids was identified in smoking blends in the fall
of 2013.76,78,114 Compounds of this group were prepared
by the manufacturers of designer drugs by analogy with
naphthoylindoles.
Indazole3carboxamides
Structural modification of aminoalkylindoles (intro
duction of an additional N atom into the heterocyclic
system and the presence of the carboxamide group) has
given rise to another group of synthetic cannabinoids,
namely, indazole3carboxamides. This modification
seems to be quite reasonable when considering the phar
macological data for diarylpyrazoles.
Many indazole3carboxamides were obtained and
tested at the laboratory headed by Makriyannis115 and the
laboratories of the pharmaceutical company "Pfizer
Inc."116,117 The latter tried various specific types of sub
stituents at the N(1) atom of the indazole ring and at the
carboxamide N atom. Many of the synthesized compounds
show high affinity for cannabinoid receptors and are CB1
receptor agonists.
The data obtained115—117 were used to prepare new
designer drugs, including indazole3carboxamides
(ACBM(N)018, ACBM(N)2201, and MDMB(N)BZF),
which came into widespread use in the spring of 2012.79,118
To date, many indazole3carboxamides containing vari
ous substituents at the carbamoyl N atom have been iden
tified on the NPS market.76,80—82
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1261
Indazole3carboxylates
Indazole3carboxylates are a new group of synthetic
cannabinoids specially manufactured as designer drugs and
appeared on the illegal market in the spring of 2014.83
Analysis of indazole3carboxylate structures
(QCBL(N)018, QCBL(N)2201, and CBL(N)2201)
clearly demonstrates that they were synthesized by analo
gy with the indole3carboxylates described above. Re
placement of the indole heterocyclic system by the ind
azole one is now a common way of modifying synthetic
cannabinoids for them to elude legal control. The unorig
inal approaches and the lack of any literature data on the
methods of synthesis, biological tests, and properties of
indazole3carboxylates unambiguously suggest that these
compounds were made at the laboratories of the manufac
turers of designer drugs.
Miscellaneous cannabinoids
This class includes heterocyclic compounds for which
the classification in use reserves no special subdivisions for
some or other reasons such as, e.g., few synthesized com
pounds, scarce data on their activity, or the accomplish
ment of a certain scheduled portion of the study of the
compounds that are currently of no pharmacological or
other interest.
Naphthoylpyrroles
This group includes 3naphthoylpyrrole derivativ
es synthesized in the molecular modeling aimed at study
ing a structure—activity relationship of canna
binoids.32,119aaa
Some of them, e.g., [5(2fluorophenyl)1pentyl1H
pyrrol3yl](naphthalen1yl)methanone (JWH307) and
[5(2methylphenyl)1pentyl1Hpyrrol3yl](naphth
alen1yl)methanone (JWH370), show high affinity for
receptors of both types.120
Some compounds of this group (e.g., JWH307) also
serve as NPS.121
Thiazolylidenes
In early 2012, the compound A836339 was identified
on the illegal NPS market.108 This structural analog of
A796260 contains a thiazolylidene moiety.
2Naphthoylbenzimidazoles
The class of miscellaneous synthetic cannabino
ids can be supplemented with a group of 2naphthoyl
benzimidazoles. A first representative of such com
pounds (BIM2201) appeared on the market in late
2013.77,78
Shevyrin and Morzherin1262 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015
Some other groups of cannabinoids
A search for new compounds capable of affecting can
nabinoid receptors still remains a topical area of research
in medicinal chemistry. Many cannabinoids with various
heterocyclic structures have been obtained in recent years.
Synthetic chemists make much effort to design compounds
that would be highly selective to CB2 receptors but would
have no psychoactive properties. To this end, various carb
oxamides were synthesized, including those based on py
ridine, 2oxo1,2dihydropyridine,122 5arylisoxazole,123
benzimidazole,124 7oxo[1,4]oxazino[2,3,4ij]quino
line,125 biphenyl,126 and tricyclic pyrazole structures.127
1,3,5Triazine derivatives128 and 3arylcarboxamide de
rivatives of 1,2dihydro2oxopyridine,129 5, 6, and 7
azaindole,130,131 and thiazole132 were tested for activity at
CB2 receptors.
The synthesis of CB1 receptor antagonists is of certain
interest. This type of activity was exhibited by 5,6diaryl
pyrazinecarboxamides and carbothioamides,133 1,2,4tri
azolones,134 and tetrahydropyrazolo[4,3c]pyridines.135
Cannabinoids that show mixed CB1/CB2activity or are
CB1 receptor agonists were also synthesized. Examples
are indol3ylquinuclidine,136 2pyridylbenzimidazole,137
indol3yl1,2,4oxadiazole,138 benzothiophene, and ben
zofuran derivatives.139
Note that far from all the compounds obtained possess
the desired pharmacological properties, and some of them
are likely to come into the illegal drug market as NPS
in future.
Conclusion
Our survey of the literature data allows some conclu
sions to be made.
First, cannabinoids are biologically active and could
be used to treat various diseases. However, the pharmaco
logical effects of these compounds are often heavily out
balanced by their psychoactive properties, which presents
a serious obstacle to the pharmacological use of canna
binoids. Their biological activity is directly related to the
effect on cannabinoid receptors of the first and second
types in the endocannabinoid system of the body. The
pharmacological activity of cannabinoids can be predict
ed in terms of their affinity for the one or other type of
receptors. The affinity of cannabinoids for CB1 receptors
directly correlates with their narcogenic potential, provid
ed that a cannabinoid is a CB1 agonist capable of crossing
the bloodbrain barrier.
Second, experimental synthetic compounds with dif
ferent cannabinoid activities were prepared to study rela
tionships between the chemical structure, pharmacologi
cal activity, and affinity of cannabinoids for CB1 and CB2
receptors and to model, using the revealed relationships,
potential drugs deprived of the negative properties of nat
ural cannabinoids. Although some of them are promising
compounds of medical interest, many synthetic cannab
inoids are much more narcogenic than THC. In most
cases, data on the synthesis and pharmacological proper
ties of new cannabinoids are available from the overt sci
entific literature and can be used to manufacture narcotic
drugs of new types.
Third, a search for efficacious drugs targeting the endo
cannabinoid system of the body remains a promising and
extensively developed branch of pharmacology. This inev
itably involves the preparation and study of new synthetic
cannabinoids whose structural diversity cannot be system
atized in terms of the traditional classification yet to be
altered. The design and synthesis of new cannabinoids
were substantially contributed by the illegal NPS market.
Fourth, some of the experimental synthetic canna
binoids that are strong CB1 receptor agonists and, accord
ingly, show narcotic activity are widely distributed as drugs
of abuse and prohibited by law. To circumvent the drug
prohibition laws, illicit traffickers continually offer syn
thetic cannabinoids of new types, whether described or
not in the scientific literature, which are structural modi
fications of the wellknown compounds.
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