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Cannabinoid chemistry: an overview

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Cannabinoid chemistry: an overview
Lumír O. Hanusˇ and Raphael Mechoulam
Department of Medicinal Chemistry and Natural Products, Medical Faculty, The Hebrew University
of Jerusalem, Ein Kerem Campus, 91120 Jerusalem, Israel
Cannabis sativa probably originates from neolithic China [1]. However the
exact period of its domestication is unknown. The first known record of the use
of cannabis as a medicine was published in China 5000 years ago in the reign
of the Emperor Chen Nung. It was recommended for malaria, constipation,
rheumatic pains, absent-mindedness and female disorders. Later its use spread
into India and other Asian countries, the Middle East, Asia, South Africa and
South America. It was highly valued in medieval Europe. In Western Europe,
particularly in England, cannabis was extensively used as a medicine during the
19th century, while in France it was mostly known as a “recreational” drug [2].
Natural cannabinoids
The first successful attempt to identify a typical cannabis constituent was
achieved by Wood et al. [3], who isolated cannabinol from the exuded resin of
Indian hemp (charas), which was analysed as C
. Another big step was
made by Cahn, who advanced the elucidation of the structure of cannabinol
[4], leaving as uncertain only the positions of a hydroxyl and a pentyl group.
Several years later Todd’s group in the UK [5, 6] and independently Adam’s
group in the USA [7] synthesized several cannabinol isomers and compared
them with the natural one. One of the synthetic isomers was identical to the
natural product. The correct structure of the first natural cannabinoid, cannabi-
nol, was thus finally elucidated. These two groups assumed that the psy-
chotropically active constituents were tetrahydrocannabinols (THCs), which
however they could not isolate in pure form and therefore they could not elu-
cidate their structures.
A second cannabis constituent, the psychotropically inactive cannabidiol,
was also isolated, but its structure was only partially clarified [8]. Synthetic
THC derivatives, which showed cannabis-like activity in animal tests, were
prepared, but they obviously differed from the active natural product, on the
basis of their UV spectrum [912].
Cannabinoids as Therapeutics
Edited by R. Mechoulam
© 2005 Birkhäuser Verlag/Switzerland
In a systematic study of the antibacterial substances in hemp Krejcˇí and
antavy´ found that an extract containing carboxylic acids was effective against
Staphylococcus aureus and other Gram-positive micro-organisms. They isolat-
ed cannabidiolic acid and reported a nearly correct structure [13, 14] (Fig. 1).
24 L.O. Hanusˇ and R. Mechoulam
Figure 1. A tentative biogenesis of the plant cannabinoids
Advances in isolation methods made possible a clarification of the chem-
istry of cannabis. In 1963 our group reisolated cannabidiol and reported its
correct structure and stereochemistry [15]. A year later we finally succeeded in
isolating pure THC (
-THC); we elucidated its structure, obtained a crys-
talline derivative and achieved a partial synthesis from cannabidiol [16]. The
absolute configuration of cannabidiol and of THC was established by correla-
tion with known terpenoids [17]. Several years later a minor psychotomimeti-
cally active constituent,
-THC, was isolated from marijuana [18]. Whether
this THC isomer is a natural compound, or an artifact formed during the dry-
ing of the plant, remains an open problem.
Several additional, non-psychotropic cannabinoids were also identified at
that time. The best known are cannabigerol [19], cannabichromene [20, 21]
and cannabicyclol [22]. For a better understanding of the biogenesis of a
cannabinoids in the plant the isolation and identification of cannabinoid acids
turned out to be essential. Alongside cannabidiolic acid, the cannabinolic and
cannabigerolic acids were identified [23], followed by two
-THC acids, A
and B [24, 25], as well as
-THC acid [26, 27] and cannabielsoic acid [28].
The decarboxylated product of cannabielsoic acid, cannabielsoin, is found in
mammals as a metabolite of cannabidiol [29]. The syntheses of some of the
cannabinoid acids have been reported [30].
A tentative pathway for the biogenesis of cannabinoids in the plant has been
published [3134]. However the only experimental support for
-THC acid
formation from cannabigerolic acid (by direct oxidocyclization and not
through cannabidiolic acid as was assumed before) has been reported by
Shoyama’s group [35]. They showed that the presence of a carboxyl group in
the substrate is essential for enzymatic cyclization of the terpene moiety. This
finding may explain the presence of THC and THC acids in certain cannabis
strains (e.g. South African) that do not contain cannabidiol or its acid [3638].
In a series of elegant publications Shoyama’s group identified an enzyme
forming cannabichromenic acid and showed that this acid is formed directly
from cannabigerolic acid [39, 40].
It is possible that some of the natural neutral cannabinoids are artifacts
formed through decarboxylation, photochemical cyclization (cannabicyclol),
oxidation (cannabielsoic acid) or isomerization (
-THC and
-THC acid) of
other constituents.
Endogenous cannabinoids
The discovery of a high-affinity, stereoselective and pharmacologically dis-
tinct cannabinoid receptor in a rat brain tissue [41] led to a search for natural
endogenous ligands in the brain, which bind to this cannabinoid receptor. We
assumed that the cannabinoid receptor in the brain is not present just to bind a
plant constituent, but to be activated by specific endogenous ligands. Our
approach involved first the synthesis of a potent labeled agonist (HU-243),
Cannabinoid chemistry: an overview 25
which made possible a sensitive bioassay. This compound is the most active
cannabinoid known so far [65]. In a standard bioassay we expected that
endogenous compounds with cannabinoid activity would displace tritiated
HU-243 bound to the central cannabinoid receptor (CB
Rat brains are too small and hence we started our isolations with porcine
brains. After nearly 2 years of tedious work, which involved numerous chro-
matographic separations, we isolated from brain an endogenous compound that
binds to the cannabinoid receptor with about the same potency as
-THC. This
endogenous ligand was named anandamide [42], a name derived from the
Sanskrit word for bliss, ananda. When administered intraperitoneally to mice it
caused reduced activity in an immobility test and in open field tests, and pro-
duced hypothermia and analgesia, a tetrad of assays typical of the psychotropic
cannabinoids [43]. Later we isolated two additional, apparently minor, endo-
genous cannabinoids, homo-γ-linoleoylethanolamide and 7,10,13,16-docosa-
tetraenoylethanolamide [44].
The existence of a peripheral cannabinoid receptor (CB
) led to the search
for a ligand to this receptor. We isolated from canine gut another arachidonic
acid derivative, 2-arachidonoyl glycerol (2-AG) [45]. At around the same time
this compound was detected in brain [46] (see Fig. 2).
Hanusˇ et al. reported a third, ether-type endocannabinoid, 2-arachidonyl
glyceryl ether (noladin ether), isolated from porcine brain [47]. It binds to the
cannabinoid receptor (K
= 21.2 ± 0.5 nM) and causes sedation, hypother-
mia, intestinal immobility and mild antinociception in mice. It binds very
weakly to the CB
receptor. The presence of this endocannabinoid in brain has
been questioned [48]. However as this type of natural glycerol derivative (an
ether group on the 2-position) is unusual, we have repeated its isolation with
an identical result (unpublished observations).
In the course of the development of a bioanalytical method to assay anan-
damide in brain and peripheral tissues, a compound with the same molecular
weight as anandamide, but with a shorter retention time, was identified as
O-arachidonoyl ethanolamine (arachidonic acid and ethanolamine joined by
an ester linkage). This compound was named virodhamine [49].
On the basis of previous structureactivity relationship studies and on the
existence in body tissues of biosynthetic precursors, Huang et al. assumed that
N-arachidonoyl-dopamine (NADA) may exist as an endogenous
“capsaicin-like” cannabinoid in mammalian nervous tissues and may possibly
bind to the vanilloid receptor VR1 [50]. They found that NADA is indeed a
natural endocannabinoid in nervous tissues, with high concentrations found in
the striatum, hippocampus and cerebellum and lower concentrations in the
dorsal root ganglion. NADA binds to the cannabinoid receptors with a 40-fold
greater selectivity for the CB
= 250 ± 130 nM) than the CB
One of the typical endocannabinoid effects is pain suppression. Some
endogenous fatty acid derivatives (palmitoylethanolamide, oleamide), which
do not bind to CB
or CB
, either enhance this effect (the so-called entourage
26 L.O. Hanusˇ and R. Mechoulam
effect) or actually show activity by themselves, presumably by binding to
as-yet unidentified cannabinoid receptors [53].
Shortly after the isolation of anandamide, its biosynthesis, metabolism and
degradation in the body were studied [54, 55].
Synthetic cannabinoid receptors agonists/antagonists
In the late 1970s Pfizer initiated a cannabinoid project aimed at novel anal-
gesic compounds. Numerous active bicyclic compounds were synthesized.
The compound chosen for clinical evaluation was CP-55,940 [56, 57]. This
compound is more potent than morphine and is at least 200-fold more potent
than its enantiomer [55]. Structural and stereochemical evaluations led to high-
ly active analogs [58]. The cannabinoid-type side effects observed with this
group of “non-classical” cannabinoids led to the termination of the project
[58]. However, these compounds helped advance the cannabinoid field as they
Cannabinoid chemistry: an overview 27
Figure 2. The main endocannabinoids
were the first cannabinoids that were widely used as labeled ligands. Indeed,
in 1988 Allyn Howlett’s group used tritium-labeled CP-55,940 for the identi-
fication of the first cannabinoid receptor [59]. [
H]CP-55,940 is now an impor-
tant tool in the study of cannabinoid receptors [60].
The need for stereospecific cannabinoid ligands led to further syntheses of
enantiomers with essentially absolute stereochemical purity. This endevour
culminated by the preparation of very potent cannabimimetic compounds [61].
Replacement of the n-pentyl side chain with a 1,1-dimethyl heptyl side chain in
one of the major active primary metabolites of
-THC, 11-hydroxy-
led to the highly active ligand 11-hydroxy-
-THC-dimethylheptyl, or HU-210.
The psychotropically inactive enantiomer, HU-211, is however analgesic,
antiemetic and is at present being evaluated as an anti-trauma agent. Both com-
pounds were synthesized with very high enantiomeric purity (99.8%) [62]. The
high degree of enantioselectivity and potency of HU-210 was demonstrated in
mice, dogs and pigeons [63, 64].
The synthetic HU-210 was used to prepare a novel probe for the cannabi-
noid receptor. Hydrogenation of this compound yielded two epimers of
5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol [65]. The equatorial
epimer (designated HU-243) binds to the cannabinoid receptor with a K
of 45 pM, and is the most potent CB
agonist described so far. Tritiated
HU-243 was used as a novel probe for the cannabinoid receptor.
An effort to find new synthetic cannabinoids with increased therapeutic
activity and few adverse side effects led to the preparation of ajulemic acid
(HU-239), an analgetic and anti-inflammatory cannabinoid [66, 67]. This com-
pound has anti-tumor effects in mice [68], binds to the peroxisome prolifera-
tor-activated receptor γ (PPARγ), a pharmacologically important member of
the nuclear receptor superfamily [69], and induces apoptosis in human T lym-
phocytes [70]. However, it binds to CB
and has activity at the level of THC in
the tetrad assay in mice [71].
A group at the Sterling pharmaceutical company prepared analogs of the
anti-inflammatory drug pravadoline, an aminoalkylindole. To their surprise
28 L.O. Hanusˇ and R. Mechoulam
Structure 1
they discovered that these compounds acted not only as cyclooxygenase
inhibitors, but also as cannabinoid agonists [72]. In vitro structureactivity
relationship studies of these compounds led to numerous new compounds with
cannabinoid receptor agonist activity [73, 74]. The best-known compound in
this series is the conformationally restricted derivative WIN-55212-2 [75]. A
binding assay in rat cerebellum membranes has been developed. It makes use
of the stereospecific radioligand [
The first potent and selective antagonist of the central cannabinoid receptor
), SR-141716A, was reported in 1994 by a group at Sanofi [76]. This
compound is not active on the peripheral cannabinoid receptor (CB
) and has
rapidly become a new tool in the study of cannabinoid receptor mechanisms
and in research on new therapeutic agents. Another novel CB
LY320135, which is not as selective as the previous one, was reported soon
Cannabinoid chemistry: an overview 29
Structure 2
Structure 3
thereafter. This substituted benzofuran reverses anandamide-mediated adeny-
late cyclase inhibition and also blocks WIN-55212-2-mediated inhibition of
N-type calcium channels [77].
The Sanofi group also described the first potent and selective antagonist of
the peripheral cannabinoid receptor (CB
), SR-144528 [78], and like the
above-mentioned CB
antagonist, it soon became a major tool in cannabinoid
research [79].
Our group reported the preparation of a CB
-selective ligand, HU-308 [80],
which is now being investigated as an anti-inflammatory drug by Pharmos, a
pharmaceutical firm. It shows no central nervous system effects due to its
essential lack of affinity for the CB
receptor. In HU-308 both phenolic groups
are blocked as methyl ethers. This is in contrast to cannabinoid CB
in which at least one of the phenolic groups has to be free.
Traumatic brain injury is a major cause of mortality and morbidity. There is
no effective drug to treat brain-injured patients. We found that on closed head
injury the amounts of 2-AG produced by the brain are increased 10-fold, and
that this endocannabinoid apparently has a neuroprotective role, as adminis-
tration of 2-AG to mice with head trauma reduces both the neurological dam-
age and the edema [81]. Numerous other groups have recorded work on vari-
30 L.O. Hanusˇ and R. Mechoulam
Structure 4
Structure 5
ous aspects of cannabinoids as neuroprotective agents (see Chapter by
Fernández-Ruiz et al. in this volume). On this basis a structurally novel, high-
ly potent CB
cannabinoid receptor agonist, BAY 38-7271, was prepared
and shown to have pronounced neuroprotective efficacy in a rat model of trau-
matic brain injury [8285].
Pharmos have developed a cannabinoid, PRS 211,096, that binds to the
peripheral cannabinoid receptor and which is being assayed for treatment of
multiple sclerosis [86].
Cannabinoid chemistry: an overview 31
Structure 7
Structure 6
Structure 8
(R)-Methanandamide (AM-356) is a chiral analog of the endocannabinoid
ligand anandamide, It is more stable than anandamide to hydrolysis by fatty
acid amide hydrolase (FAAH), as the methyl group adjacent to the amide moi-
ety apparently interferes with the enzyme. It has a K
value of 20 ± 1.6 nM for
the CB
receptor [87]. The K
value for binding to the CB
receptor from
mouse spleen is 815 nM [88]. Thus (R)-methanandamide has a high selectivi-
ty for the CB
6-Iodo-pravadofine (AM-630), an aminoalkylindole, attenuates the ability
of a number of cannabinoids to inhibit electrically evoked twitches of vas def-
erens isolated from mouse [89]. AM-630 behaves as a competitive antagonist
of cannabinoid receptor agonists in the guinea-pig brain [90]. AM-630 also
antagonizes the ability of the cannabinoid agonist WIN-55212-2 to stimulate
S]thio)triphosphate ([
S]GTPγS) binding in mouse
brain membrane preparations [91].
Gatley et al. [92] have developed a novel radioligand, [
I]AM-281, struc-
turally related to the CB
-selective antagonist SR-141716A, that is suitable for
in vivo studies of the central cannabinoid receptor and for imaging this recep-
tor in the living human brain [92].
32 L.O. Hanusˇ and R. Mechoulam
Structure 9
Scientists at the University of Connecticut have synthesized and studied a
series of aminoalkylindoles as selective CB
agonists. The compounds are stat-
ed to be useful for the treatment of pain, glaucoma, multiple sclerosis and other
diseases and disorders. Compound AM-1241 has a high affinity for the CB
receptor in a mouse spleen preparation (K
= 3.4 ± 0.5 nM), with good selectiv-
ity versus the CB
receptor in a rat brain preparation (K
= 280 ± 41 nM). This
compound has recently been found to inhibit neuropathic pain in rodents [93].
AM-2233, a novel aminoalkylindole CB
agonist, was found to have a
greater potency than WIN-55212-2 in assays in vitro, but has a similar poten-
cy to it in a mouse locomotor assay. It was suggested that its behavioral effects
could have been mediated, in part, via an action on another receptor type in
addition to the CB
receptor. AM-2233 represents the first agonist CB1 recep-
tor ligand (K
= 0.4 nM) with potential as an in vivo imaging agent for this
receptor [94, 95]. Stoit et al. [96] have reported the syntheses and biological
activities of potent pyrazole-based tricyclic CB
receptor antagonists. One can
find additional information on cannabinoid receptor agonists and antagonists
in Barth’s review [97].
Gallant et al. [98] have described two indole-derived compounds (see struc-
tures below), with binding potency for the human peripheral cannabinoid
receptor (CB
) in the nanomolar region, They are highly selective.
A new series of rigid 1-aryl-1,4-dihydroindeno[1, 2-c]pyrazole-3-carbox-
amides was recently designed [99]. Seven of the new compounds displayed
very high in vitro CB
-binding affinities. Four compounds showed very high
selectivity for the CB
Cannabinoid structureactivity relationship data have indicated that the
cannabinoid side chain and the phenolic hydroxyl are key elements in CB
receptor recognition. To test this hypothesis, the 1-deoxy analog, JWH-051, of
the very potent cannabinoid 11-hydroxy-
-THC-dimethylheptyl (HU-210)
was prepared and the affinity of this compound for the CB
receptor was deter-
mined [100]. Contrary to expectations, this 1-deoxy analog still had high affin-
ity for the CB
receptor (K
= 1.2 ± 0.1 nM) and even greater affinity for the
Cannabinoid chemistry: an overview 33
Structure 10
receptor (K
= 0.032 ± 0.19 nM). On the basis of these data, it is apparent
that a phenolic hydroxyl group is not essential for cannabinoid activity.
To obtain selective ligands for the CB
and to explore the structureactivi-
ty relationship of the 1-deoxy-cannabinoids, the same research group
described the synthesis and pharmacology of 15 1-deoxy-
-THC analogues
[101]. Five of these analogues had high affinity (K
20 nM) for the CB
receptor. Four of them also had low affinity for the CB
receptor (K
295 nM).
-THC (JWH-133) had very high affinity
for the CB
receptor (K
= 3.4 ± 1.0 nM) and low affinity for the CB
= 677 ± 132 nM).
In view of the importance of the CB
receptor, three series of CB
cannabinoid receptor ligands, 1-methoxy-, 1-deoxy-11-hydroxy- and
-THCs, were designed [102]. All of these com-
pounds have greater affinity for the CB
receptor than for the CB
however, only 1-methoxy-3-(1',1'-dimethylhexyl)-
-THC (JWH-229) had
essentially no affinity for the CB
receptor (K
= 3134 ± 110 nM) with high
affinity for CB
= 18 ± 2 nM).
34 L.O. Hanusˇ and R. Mechoulam
Structure 12
Structure 11
Recently the discovery of a further class of diarylpyrazolines with high
potency and selectivity for the CB
receptor was described [103]. These com-
pounds were found to be CB
antagonists. SLV319 was found to be a potent
antagonist (K
= 7.8 nM) close to that of the Sanofi compound
SR-141716A, with more than 1000-fold selectivity against CB
Additional synthetic compounds that bind to the CB
and/or CB
have been mentioned in patents. These were recently reviewed by Hertzog
Cannabinoid chemistry: an overview 35
Structure 13
Structure 14
Novartis AG has recently filed a patent application on a series of quinazo-
lines as cannabinoid agonists useful for the treatment of pain, osteoarthritis,
rheumatoid arthritis and glaucoma, among other indications [105]. Compound
1 binds to both CB
= 34 nM) and CB
= 11 nM). The patent applica-
tion refers to the compound as having CB
agonist activity. Additionally, this
compound has been shown to be active in a rodent neuropathic pain model
when administered at an oral dose of 0.5 mg/kg.
The University of Connecticut has disclosed a series of indazole derivatives
that have been found to act as agonists of cannabinoid receptors [106]. The
compounds exhibit a range of selectivities for CB
over CB
. Compound 2,for
instance, exhibited K
values of 2.28 and 0.309 nM for the CB
and CB
tors, respectively. This compound produced dose-dependent anti-nociception
to thermal stimulus in rats. The compound reduced locomotor activity in rats
after intravenous administration, an effect attributed to activation of the CB
A series of aromatic CB
agonists has been disclosed by the Schering-Plough
Research Institute [107, 108]. The compounds are reported to have anti-inflam-
36 L.O. Hanusˇ and R. Mechoulam
Structure 15
Structure 16
matory and immunomodulatory activities, and to be active in cutaneous T cell
lymphoma, diabetes mellitus and other indications. Compound 3 is stated to
bind to CB
with a K
value in the range 0.110 nM.
Researchers at AstraZeneca have disclosed a series of benzimidazoles and
azabenzimidazoles to be CB
agonists [109]. The compounds are described as
useful in the treatment of pain, cancer, multiple sclerosis, Parkinson’s disease,
Huntington’s chorea, transplant rejection and Alzheimer’s disease. Cannabinoid
receptor selectivity data are provided for some of the new compounds. For
instance, compound 4 binds to CB
= 3.1 nM) with much greater affinity
than to CB
= 2.8 µM). No in vivo data are provided for the compounds.
The University of Connecticut has disclosed a series of biphenyls as
cannabinoid modulators [110]. These non-classical cannabinoids are described
as useful for the treatment of peripheral pain, neuropathy, neurodegenerative
diseases and other indications. Several of the compounds were found to bind
selectively to the CB
receptor. For instance, compound 5 binds to CB
with a
value of 0.8 nM and to CB
with a K
value of 241 nM.
Cannabinoid chemistry: an overview 37
Structure 17
Structure 18
The Virginia Commonwealth University has filed a patent application on a
series of resorcinol derivatives as selective CB
agonists useful for the treatment
of pain, inflammation and autoimmune diseases [111]. Binding data for the
compounds to CB
and CB
are provided, and the compounds were assayed for
in vivo activity in mouse tail-flick, spontaneous activity and rectal temperature
assays. Compound 6 had K
values of 40 and 0.8 nM, respectively, for the CB
and CB
receptors. In addition, this compound was assessed by intravenous
administration and exhibited ED
values of 2.7, 2.4 and 3.6 mg/kg in the spon-
taneous activity, tail-flick and rectal temperature assays, respectively.
The University of Connecticut has disclosed a series of dihydrotetrazines and
derivatives as CB
agonists [112]. Compound 7 is reported to be a potent CB
agonist (K
= 19 nM) with 88-fold selectivity for the CB
over the CB
Such compounds are reported to be useful in the treatment of pain, glaucoma,
multiple sclerosis, Parkinson’s disease, Alzheimer’s disease and other disorders.
Shionogi has also disclosed two series of thiazine-containing CB
of which compounds 8 and 9 are examples [113, 114]. Selectivity data for sev-
eral of the compounds with regard to CB
affinities are described. For
38 L.O. Hanusˇ and R. Mechoulam
Structure 19
Structure 20
Structure 21
example, compound 8 binds to CB
with a K
value of 0.3 nM and a K
of >5000 nM for CB
. Compound 9 displayed a K
value of 1.2 nM at the CB
receptor and 80 nM at the CB
receptor. When dosed orally at 100 mg/kg in a
mouse pruritis model, this compound reduced scratching by 98% relative to
control animals.
Shionogi has disclosed a series of amide-containing CB
modulators stated
to be useful in the treatment of inflammation, nephritis, pain, allergies,
rheumatoid arthritis, multiple sclerosis, brain tumors and glaucoma [115].
Compound 10 was found to bind to the CB
receptor with a K
value of 4 nM,
with very little affinity for CB
< 5 µM).
Recently 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives (11) were
synthesized as new ligands of cannabinoid receptors [116]. Some of these com-
pounds possess a greater affinity for the CB
receptor than for the CB
tor. Compound 7-chloro-N-cyclohexyl-1-(2-morpholin-4-ylethyl)-1,8-naph-
thyridin-4(1H)-on-3-carboxamide (12) revealed a good CB
selectivity (CB
= 1 µM; CB
= 25 ± 1.8 nM).
Indole derivatives were prepared and tested for their CB
and CB
affinities [117]. Three new highly selective CB
receptor agonists were identi-
fied, namely JWH-120 (CB
, K
= 1054 ± 31 nM; CB
, K
= 6.1 ± 0.7 nM),
JWH-151 (CB
, K
>10000 nM; CB
, K
= 30 ± 1.1 nM) and JWH-267 (CB
= 381 ± 16 nM; CB
, K
= 7.2 ± 0.14 nM).
Cannabinoid chemistry: an overview 39
Structure 22
Structure 23
C. sativa L. has been used throughout history not only for its fiber, but also as
a medicinal plant. It has been the object of scientific research over the past 150
years. After the isolation of the plant’s constituents, biochemical work led to
the identification of two receptors and of endogenous cannabinoids. Over the
last decade numerous synthetic agonists and antagonists have been prepared.
We may be approaching an important goal in cannabinoid research – the use
of cannabinoids in medicine – which has been the dream of several generations
of scientists.
40 L.O. Hanusˇ and R. Mechoulam
Structure 25
Structure 24
1 Li HL (1974) An archeological and historical account of cannabis in China. Econ Bot 28: 437448
2 Wood TB, Spivey WTN, Easterfield TH (1896) Charas, the resin of Indian hemp. J Chem Soc 69:
3 Wood TB, Spivey WTN, Easterfield TH (1899) Cannabinol. Part I. J Chem Soc 75: 2036
4 Cahn RS (1932) Cannabis indica resin, Part III. The constitution of Cannabinol. J Chem Soc
5 Jacob A, Todd AR (1940) Cannabis indica. Part II. Isolation of cannabidiol from egyptian hashish.
Observations on the structure of cannabinol. J Chem Soc 649–653
6 Ghosh R, Todd AR, Wilkinson S (1940) Cannabis indica, Part V. The synthesis of cannabinol. J
Chem Soc 13931396
7 Adams R, Baker BR, Wearn RB (1940) Structure of cannabinol. III. Synthesis of
cannabinol,1-Hydroxy-3-n-amyl-6,6,9-trimethyl-6-dibenzopyran. J Am Chem Soc 62:
8 Adams R, Wolff H, Cain CK, Clark JH (1940) Structure of cannabidiol. V. Position of the alicyclic
double bonds. J Am Chem Soc 62: 22152219
9 Adams R, Loewe S, Pease DC, Cain CK, Wearn RB, Baker BR, Wolff H (1940) Structure of
cannabidiol. VIII. Position of the double bonds in cannabidiol. Marihuana activity of tetrahydro-
cannabinols. J Am Chem Soc 62: 25662567
10 Adams R, Baker BR (1940) Structure of cannabidiol. VII. A method of synthesis of a tetrahydro-
cannabinol which possesses marihuana activity. J Am Chem Soc 62: 24052408
11 Adams R, Pease DC, Cain CK, Baker BR, Clark JH, Wolff H, Wearn RB (1940) Conversion of
cannabidiol to a product with marihuana activity. A type reaction fo synthesis of analogous sub-
stances. Conversion of cannabidiol to cannabinol. J Am Chem Soc 62: 22452246
12 Ghosh R, Todd AR, Wilkinson S (1940) Cannabis indica, Part IV. The synthesis of some tetrahy-
drodibenzopyran derivatives. J Chem Soc 11211125
13 Krejcˇí Z, S
antavy´ F (1955) Isolace dalsˇích látek z listí indického konopí Cannabis sativa L. Acta
Univ Palacki Olomuc 6: 5966
14 Kabelík J, Krejcˇí Z, S
antavy´ F (1960) Cannabis as a medicament. Bull Narc 12: 523
15 Mechoulam R, Shvo Y (1963) The structure of cannabidiol. Tetrahedron 19: 20732078
16 Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent
of hashish. J Am Chem Soc 86: 16461647
17 Mechoulam R, Gaoni Y (1967) The absolute configuration of
-tetrahydrocannabinol, the major
active constituent of hashish. Tetrahedron Lett 8: 11091111
18 Hively RL, Mosher WA, Hoffmann FW (1966) Isolation of trans-
- tetrahydrocannabinol from
marijuana. J Am Chem Soc 88: 18321833
19 Gaoni Y, Mechoulam R (1964) The structure and synthesis of cannabigerol, a new hashish con-
stituent. Proc Chem Soc 82
20 Gaoni Y, Mechoulam R (1966) Cannabichromene, a new active principle in hashish. Chem
Commun 20–21
21 Claussen U, v Spulak F, Korte F (1966) Zur chemischen Klassifizierung von Pflanzen XXXI.
Haschisch X. Cannabichromen, ein neuer Haschisch-Inhaltsstoff. Tetrahedron 22: 14771479
22 Crombie L, Ponsford R (1968) Hashish components. Photochemical production of cannabicyclol
from cannabichromene. Tetrahedron Lett 9: 57715772
23 Mechoulam R, Gaoni Y (1965) The isolation and structure of cannabinolic, cannabidiolic and
cannabigerolic acids. Tetrahedron 21: 12231229
24 Korte F, Haag M, Claussen U (1966) Tetrahydrocannabinol-carbonsäure, ein neuer
Haschisch-Inhaltsstoff. Angew Chem 77, 862
25 Yamauchi T, Shoyama Y, Aramaki H, Azuma T, Nishioka I (1967) Tetrahydrocannabinolic acid a
genuine substance of tetrahydrocannabinol. Chem Pharm Bull 15, 1075
26 Mechoulam R, Ben-Zvi Z, Yagnitinsky B, Shani A (1969) A new tetrahydrocannabinolic acid.
Tetrahedron Lett 10: 23392341
27 Krejcˇí Z, S
antavy´ F (1975) Isolation of two new cannabinoid acids from Cannabis sativa L. of
Czechoslovak origin. Acta Univ Olomuc, Fac Med 74: 161166
28 Shani A, Mechoulam R (1974) Cannabielsoic acids. Isolation and synthesis by a novel oxidative
cyclization. Tetrahedron 30: 24372446
29 Gohda H, Narimatsu S, Watanabe K, Yamamoto I, Yoshimura H (1987) The formation mechanism
Cannabinoid chemistry: an overview 41
of cannabielsoin from cannabidiol with guinea-pig hepatic- microsomal enzymes. J Pharm Sci 76:
30 Mechoulam R, Ben-Zvi Z (1969) Carboxylation of resorcinols with methyl magnesium carbonate.
Synthesis of cannabinoid acids. Chem Commun 343344
31 Mechoulam R, Gaoni Y (1967) Recent advances in the chemistry of hashish. In: L Zechmeister
(ed.): Progress in the chemistry of organic natural products (Fortschritte der Chemie Organischer
Naturstoffe), vol. XXV, Springer Verlag, Wien, 175213
32 Mechoulam R, ed (1973) Marijuana. Chemistry, Metabolism, Pharmacology and Clinical Effects.
Academic Press, New York
33 Turner CE, Elsohly MA, Boeren EG (1980) Constituents of Cannabis sativa L. 17. A review of the
natural constituents. J Nat Prod 43: 169234
34 Hanusˇ L (1987) Biogenesis of cannabinoid substances in the plant. Acta Univ Palacki Olomuc, Fac
Med 116: 4753
35 Taura F, Morimoto S, Shoyama Y, Mechoulam R (1995) First direct evidence for the mechanism
of delta(1)-tetrahydrocannabinolic acid biosynthesis. J Am Chem Soc 117: 97669767
36 Turner CE, Hadley K (1973) Constituents of Cannabis sativa L. II. Absence of cannabidiol in an
African variant. J Pharm Sci 62: 251255
37 Krejcˇí Z, Hanusˇ L, Yoshida T, Braenden OJ (1975) The effect of climatic and ecologic conditions
upon the formation and the amount of cannabinoid substances in the cannabis of various prove-
nance. Acta Univ Olomuc, Fac Med 74: 147160
38 Holley JH, Hadley KW, Turner CE (1975) Constituents of Cannabis sativa L. XI: Cannabidiol and
cannabichromene in samples of known geographical origin. J Pharm Sci 64: 892895
39 Morimoto S, Komatsu K, Taura F, Shoyama Y (1997) Enzymological evidence for
cannabichromenic acid biosynthesis. J Nat Prod 60: 854857
40 Kushima H, Shoyama Y, Nishioka I (1980) Cannabis. XII. Variations of cannabinoid contents in
several strains of Cannabis sativa L. with leaf-age, season and sex. Chem Pharm Bull 28: 594–598
41 Devane WA, Dysarz FA 3rd Johnson MR, Melvin LS, Howlett AC (1988) Determination and char-
acterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34: 605613
42 Devane WA, Hanusˇ L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum
A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the
cannabinoid receptor. Science 258: 19461949
43 Fride E, Mechoulam R (1993) Pharmacological activity of the cannabinoid receptor agonist, anan-
damide, a brain constituent. Eur J Pharmacol 231: 313314
44 Hanusˇ L, Gopher A, Almog S, Mechoulam R (1993) Two new unsaturated fatty acid
ethanolamides in brain that bind to the cannabinoid receptor. J Med Chem 36: 30323034
45 Mechoulam R, Ben-Shabat S, Hanusˇ L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A,
Almog S, Martin BR, Compton DR et al. (1995) Identification of an endogenous 2-monoglyc-
eride, present in canine gut, that binds to the peripheral cannabinoid receptors. Biochem
Pharmacol 50: 8390
46 Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995)
2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochem
Biophys Res Commun 215: 8997
47 Hanusˇ L, Abu-Lafi S, Fride E, Breuer A, Shalev DE, Kustanovich I, Vogel Z, Mechoulam R (2001)
2-Arachidonyl glyceryl ether, a novel endogenous agonist of the cannabinoid CB
receptor. Proc
Natl Acad Sci USA 98: 36623665
48 Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku K, Sugiura T (2003)
Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of
various mammalian species. J Neurochem 85: 13741381
49 Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao JQ, Nomikos GG, Carter P,
Bymaster FP, Leese AB, Felder CC (2002) Characterization of a novel endocannabinoid, virod-
hamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301: 10201024
50 Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros
TJ, Krey JF, Chu CJ et al. (2002) An endogenous capsaicin-like substance with high potency at
recombinant and native vanilloid VR1 receptors Proc Natl Acad Sci USA 99: 84008405
51 Bezuglov V, Bobrov M, Gretskaya N, Gonchar A, Zinchenko G, Melck D, Bisogno T, Di Marzo
V, Kuklev D, Rossi JC et al. (2001) Synthesis and biological evaluation of novel amides of polyun-
saturated fatty acids with dopamine. Bioorg Med Chem Lett 11: 447449
52 Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V
42 L.O. Hanusˇ and R. Mechoulam
(2000) N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of
anandamide inactivation with cannabimimetic activity in vitro and in vivo. J Biochem 351:
53 Walker JM, Krey JF, Chu CJ, Huang SM (2002) Endocannabinoids and related fatty acid deriva-
tives in pain modulation. Chem Phys Lipids 121: 159172
54 Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli D (1994)
Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature
372: 68691
55 Burstein SH, Rossetti RG, Yagen B, Zurier RB (2000) Oxidative metabolism of anandamide.
Prostag Oth Lipid M 61: 2941
56 Johnson MR, Melvin LS (1983) 2-Hydroxy-4-(substituted) phenyl cycloalkanes and derivatives.
US Patent 4,371,720, Pfizer Inc
57 Melvin LS, Johnson MR, Milne GM (1983) A cannabinoid derived analgesic (CP-55,940). In:
Abstracts of Papers, 186th Natl. Meet. American Chemical. Soc., Washington, D.C., August 1983.
American Chemical Society, Washington, D.C., Abstr. MEDI, 2
58 Johnson MR, Melvin LS (1986) The discovery of nonclassical cannabinoid analgetics. In: R
Mechoulam (ed.): Cannabinoids as therapeutic agents. CRC Press, Boca Raton, FL, pp 121145
59 Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC (1988) Determination and charac-
terization of a cannabinoid receptor in rat-brain. Mol Pharmacol 34: 605613
60 Gerard CM, Mollereau C, Vassart G, Parmentier M (1991) Molecular-cloning of a human cannabi-
noid receptor which is also expressed in testis. J Biochem 279: 129134
61 Mechoulam R, Feigenbaum JJ, Lander N, Segal M, Jarbe TUC, Hiltunen AJ, Consroe P (1988)
Enantiomeric cannabinoids: stereospecificity of psychotropic activity. Experientia 44: 762764
62 Mechoulam R, Lander N, Breuer A, Zahalka J (1990) Synthesis of the individual, pharmacologi-
cally distinct, enantiomers of a tetrahydrocannabinol derivative. Tetrahedron: Asymmetry 1:
63 Little PJ, Compton DR, Mechoulam R, Martin B (1989) Stereochemical effects of
11-OH-delta-8-THC-dimethylheptyl in mice and dogs. Pharmacol Biochem Behavior 32:
64 Järbe TUC, Hiltunen AJ, Mechoulam R (1989) Stereospecificity of the discriminative stimulus
functions of the dimethylheptyl homologs of 11-OH-delta-8-tetrahydrocannabinol in rats and
pigeons. J Pharmacol Exper Ther 250: 10001005
65 Devane WA, Breuer A, Sheskin T, Jarbe TUC, Eisen M, Mechoulam R (1992) A novel probe for
the cannabinoid receptor. J Med Chem 35: 20652069
66 Burstein SH, Audette CA, Breuer A, Devane WA, Colodner S, Doyle A, Mechoulam R (1992)
Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte
antiadhesion activities. J Med Chem 35: 31353141
67 Burstein SH (2000) Ajulemic Acid (CT3): A potent analog of the acid metabolites of THC. Curr
Pharmaceut Design 6: 13391345
68 Recht LD, Salmonsen R, Rosetti R, Jang T, Pipia G, Kubiatowski T, Karim P, Ross AH, Zurier R,
Litofsky NS, Burstein S (2001) Antitumor effects of ajulemic acid (CT3), a synthetic non-psy-
choactive cannabinoid. Biochem Pharmacol 62: 755763
69 Liu JL, Li H, Burstein SH, Zurier RB, Chen JD (2003) Activation and binding of peroxisome pro-
liferator-activated receptor γ by synthetic cannabinoid ajulemic acid. Mol Pharmacol 63: 983992
70 Bidinger B, Torres R, Rossetti RG, Brown L, Beltre R, Burstein S, Lian JB, Stein GS, Zuriera RB
(2003) Ajulemic acid, a nonpsychoactive cannabinoid acid, induces apoptosis in human T lym-
phocytes. Clin Immunol 108: 95102
71 Sumariwalla PF, Gallily R, Tchilibon S, Fride E, Mechoulam R, Feldmann M (2004) A novel syn-
thetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine
collagen-induced arthritis. Arthritis Rheum 50: 985998
72 Bell MR, D’Ambra TE, Kumar V, Eissenstat MA, Herrmann JL Jr, Wetzel JR, Rosi D, Philion RE,
Daum SJ, Hlasta DJ et al. (1991) Antinociceptive (aminoalkyl)indoles. J Med Chem 34:
73 D’Ambra TE, Estep KG, Bell MR, Eissenstat MA, Josef KA, Ward SJ, Haycock DA, Baizman
ER, Casiano FM, Beglin NC et al. (1992) Conformationally restrained analogs of pravadoline:
nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor. J
Med Chem 35: 124135
74 Eissenstat MA, Bell MR, D’Ambra TE, Alexander EJ, Daum SJ, Ackerman JH, Gruett MD,
Cannabinoid chemistry: an overview 43
Kumar V, Estep KG, Olefirowicz EM et al. (1995) Aminoalkylindoles: structure-activity relation-
ships of novel cannabinoid mimetics. J Med Chem 38: 30943105
75 Haycock DA, Kuster JE, Stevenson JI, Ward SJ, D’Ambra T (1990) Characterization of
aminoalkylindole binding: selective displacement by cannabinoids. Probl Drug Depend NIDA Res
Monogr 105: 304305
76 Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani
J, Néliat G, Caput D et al. (1994) SR141716A, a potent and selective antagonist of the brain
cannabinoid receptor. FEBS Lett 350: 240244
77 Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, Cullinan GJ, Hunden DC,
Johnson DW, Chaney MO et al. (1998) LY320135, a novel cannabinoid CB1 receptor antagonist,
unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp
Ther 284: 291297
78 Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, Oustric D, Sarran M,
Bouaboula M, Calandra B et al. (1998) SR 144528, the first potent and selective antagonist of the
CB2 cannabinoid receptor. J Pharmacol Exp Ther 284: 644650
79 Griffin G, Wray EJ, Tao Q, McAllister SD, Rorrer WK, Aung M, Martin BR, Abood ME (1999)
Evaluation of the cannabinoid CB
receptor-selective antagonist, 2 SR144528: further evidence
for cannabinoid CB
receptor absence in the rat central nervous system. Eur J Pharmacol 377:
80 Hanusˇ L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Fride E, Mechoulam R
(1999) HU-308: A specific agonist for CB
, a peripheral cannabinoid receptor. Proc Natl Acad Sci
USA 96: 1422814233
81 Panikashvili D, Simeonidou C, Ben-Shabat S, Hanusˇ L, Breuer A, Mechoulam R, Shohami E
(2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:
82 Mauler F, Mittendorf J, Horváth E, De Vry J (2002) Characterization of the diarylether sul-
fonylester (–)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4- trifluoro-1-sulfonate (BAY
38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. J Pharmacol
Exp Ther 302: 359368
83 De Vry J, Jentzsch KR (2002) Discriminative stimulus effects of BAY 38-7271, a novel cannabi-
noid receptor agonist. J Pharmacol Exp Ther 457: 147152
84 Mauler F, Hinz V, Augstein KH, Fassbender M, Horvath E (2003) Neuroprotective and brain
edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Res 989:
85 Mauler F, Horváth E, De Vry J, Jäger R, Schwarz T, Sandmann S, Weinz C, Heinig R, Böttcher M
(2003) BAY 38-7271: A Novel Highly Selective and Highly Potent Cannabinoid Receptor Agonist
for the Treatment of Traumatic Brain Injury. CNS Drug Reviews 9: 343358
86 Pharmos Corp. (2002) Bicyclic cannabinoid. Poster, Society for Neuroscience 32nd Annual
Meeting, 37 November 2002, Orlando, FL
87 Abadji V, Lin S, Taha G, Griffin G, Stevenson LA, Pertwee RG, Makriyannis A (1994)
(R)-Methanandamide: A chiral novel anandamide possessing higher potency and metabolic sta-
bility. J Med Chem 37: 18891893
88 Khanolkar AD, Abadji V, Lin S, Hill WAG, Taha G, Abouzid K, Meng Z, Fan P, Makriyannis A
(1996) Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand. J
Med Chem 39: 45154519
89 Pertwee R, Griffin G, Fernando S, Li X, Hill A, Makriyannis A (1995) AM630, a competitive
cannabinoid receptor antagonist. Life Sci 56: 19491955
90 Hosohata K, Quock RM, Hosohata Y, Burkey TH, Makriyannis A, Consroe P, Roeske WR,
Yamamura HI (1997) AM630 is a competitive cannabinoid receptor antagonist in the guinea pig
brain. Life Sci 61, PL115PL118
91 Hosohata Y, Quock RM, Hosohata K, Makriyannis A, Consroe P, Roeske WR, Yamamura HI
(1997) AM630 antagonism of cannabinoid-stimulated [S-35]GTP gamma S binding in the mouse
brain. Eur J Pharmacol 321, R1R3
92 Gatley SJ, Lan R, Volkow ND, Pappas N, King P, Wong CT, Gifford AN, Pyatt B, Dewey SL,
Makriyannis A (1998) Imaging the Brain Marijuana Receptor: Development of a radioligand that
binds to cannabinoid CB1 receptors in vivo. J Neurochem 70: 417423
93 Ibrahim MM, Deng H, Zvonok A (2003) Activation of CB
cannabinoid receptors by AM1241
inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS.
44 L.O. Hanusˇ and R. Mechoulam
Proc Natl Acad Sci USA 100: 1052910533
94 Luk T, Jin WZ, Zvonok A, Lu D, Lin XZ, Chavkin C, Makriyannis A, Mackie K (2004)
Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid recep-
tor agonist. Br J Pharm 142: 495500
95 Gifford AN, Makriyannis A, Volkow ND, Gatley SJ (2002) In vivo imaging of the brain cannabi-
noid receptor. Chem Phys Lipids 121: 6572
96 Stoit AR, Lange JH, Hartog AP, Ronken E, Tipker K, Stuivenberg HH, Dijksman JA, Wals HC,
Kruse CG (2002) Design, synthesis and biological activity of rigid cannabinoid CB1 receptor
antagonists. Chem Pharm Bull 50: 11091113
97 Barth F (1998) Cannabinoid receptor agonists and antagonists. Expert Opin Ther Patents 8:
98 Gallant M, Dufresne C, Gareau Y, Guay D, Leblanc Y, Prasit P, Rochette C, Sawyer N, Slipetz
DM, Tremblay N et al. (1996) New class of potent ligands for the human peripheral cannabinoid
receptor. Bioorg Med Chem Lett 6: 22632268
99 Mussinu JM, Ruiu S, Mule AC, Pau A, Carai MAM, Loriga G, Murineddu G, Pinna GA (2003)
Tricyclic pyrazoles. part 1: Synthesis and biological evaluation of novel 1,4-dihydroinde-
no[1,2-c]pyrazol-based ligands for CB1 and CB2 cannabinoid receptors. Bioorg Med Chem 11:
100 Huffman JW, Yu S, Showalter V, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD,
Reggio PH (1996) Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic
hydroxyl with high affinity for the CB2 receptor. J Med Chem 39: 38753877
101 Huffman JW, Liddle J, Yu S, Aung MM, Abood ME, Wiley JL, Martin BR (1999)
-THC and related compounds: Synthesis of selective ligands
for the CB
receptor. Bioorg Med Chem 7: 29052914
102 Huffman JW, Bushell SM, Miller JRA, Wiley JL, Martin BR (2002) 1-methoxy-,1-deoxy-
11-hydroxy- and 11-Hydroxy-1-methoxy-
-tetrahydrocannabinols: New selective ligands for
the CB2 receptor. Bioorg Med Chem 10: 41194129
103 Lange JHM, Coolen HKAC, van Stuivenberg HH, Dijksman JAR, Herremans AHJ, Ronken E,
Keizer HG, Tipker K, McCreary AC, Veerman W et al. (2004) Synthesis, biological properties,
and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective
CB(1) cannabinoid receptor antagonists. J Med Chem 47: 627643
104 Hertzog DL (2004) Recent advances in the cannabinoids. Expert Opin Ther Patents 14:
105 Brain C T, Dziadulewicz E K, Hart T W (2003) Chinazolinonderivate und deren verwendung als
CB-agonisten. Novartis AG (CH); Novartis Pharma GMBH (AT): WO03066603.
106 Makriyannis A, Liu Q (2003) Heteroindane: Eine neue klasse hochwirksamer cannabimimetis-
cher liganden. Univ. Connecticut (US): WO03035005.
107 Kozlowski J A, Shankar B B, Shih N Y, Tong L (2004) Cannabinoid receptor agonists. Schering
Corp. (US): WO2004000807.
108 Kozlowski J A, Shih N Y, Lavey B J, Rizvi R K, Shankar B B, Spitler J M, Tong L, Wolin R,
Wong M K (2004) Cannabinoid receptor ligands. Schering Corp. (US): WO2004014825.
109 Page D, Walpole Ch, Yang H (2004) Preparation of benzimidazolecarboxamides as CB2 receptor
agonists for treating pain and other disorders. AstraZeneca AB (Swed.): WO04035548
110 Makriyannis, A., Lai, X Z, Lu D (2004) Preparation of novel biphenyl and biphenyl-like cannabi-
noids with binding affinities for the CB1 and CB2 cannabinoid receptor. Univ. Connecticut (US):
111 Martin B R, Razdan R K (2003) Cannabinoids. Virginia Commonwealth Univ. (US):
112 Makriyannis A, Deng H (2002) Novel cannabimimetic ligands. Univ. Connecticut (US):
113 Kai H, Murashi T, Tomida M (2002) Medicinal composition containing 1,3-thiazine derivative.
Shionogi & Co. Ltd (JP): WO02072562.
114 Yasui K, Morioka Y, Hanasaki K (2002) Antipruritics. Shionogi & Co. Ltd (JP): WO03070277.
115 Tada Y, Iso Y, Hanasaki K (2002) Pyridone derivative having affinity for cannabinoid 2-type
receptor. Shionogi & Co. Ltd (JP): WO02053543.
116 Ferrarini PL, Calderone V, Cavallini T, Manera C, Saccomanni G, Pani L, Ruiu S, Gessa GL
(2004) Synthesis and biological evaluation of 1,8-naphthyridin- 4(1H)-on-3-carboxamide deriv-
atives as new ligands of cannabinoid receptor. Bioorg Med Chem 12: 19211933
Cannabinoid chemistry: an overview 45
117 Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, Thompson ALS, Bushell S, Tartal C,
Hurst DP et al. (2005) Structure–activity relationships for 1-alkyl-3-(1- naphthoyl)indoles at the
cannabinoid CB
and CB
receptors: steric and electronic effects of naphthoyl substituents. New
highly selective CB
receptor agonists. Bioorg Med Chem 13: 89112
46 M. Maccarrone
... is the psychoactive component of the cannabis plant (Hanuš & Mechoulam, 2005). THC is the cannabinoid which gives users the feeling of being high. ...
Full-text available
Climate change is posing a significant threat to textile fibres. Research has shown how increased temperatures, drought and extreme weather influences the availability of raw materials for fashion. Climate change does affect textile fibres, but on the other hand, the fashion industry increases the prospects of global warming. The industry contaminates freshwater and uses an extensive amount of chemicals, pesticides and insecticides. This study aims to determine how hemp as a textile fibre can persevere under a changing climate and become a less polluting textile for the future apparel industry. By analysing and combining existing studies targeted on the cultivation and processing of hemp crops to textile fibres, the study answers: What are the impacts, challenges and opportunities of climate change on hemp fibres? Derived from a review of the literature on hemp's preferred climate and climate change data gathered from the Intergovernmental Panel on Climate Change (IPCC) reports and the Köppen Climate Classification, a predictive analysis was formed. Next to that, possible implications, opportunities and challenges hemp will face as a textile of the future are discussed. The results of this study emphasise how hemp is not only a sustainable alternative for the current most used fibres but also exceeds those fibres in climate change resistance. Given this, it is recommended that fashion brands use hemp as a key material in the future. Further research is needed to identify other factors that could secure hemp against climate change, such as seawater cultivation, hydroponic farms and the research into climate-resistant hemp strains. Next to that, the thesis can be enriched by fashion-related business cases and local supply chain case studies.
... Preserved records of cannabis use in medicine can be found in China and are nearly 5000 years old (Hanuš and Mechoulam, 2005). The healing properties of cannabis products have been recognized for millennia, but because of the psychoactive nature of the major active substance Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and the fact that cannabis is the most commonly used illegal narcotic substance not only in Europe, but around the world, this substance has been criminalized for a long time in most countries in the world (Wilkinson et al., 2003;Hanuš, 2009). ...
In the last decades, there has been a significant increase in the number of lifestyle and auto-immune diseases, such as various cancers or multiple sclerosis. In countries where cannabis is decriminalized for medical purposes, it is most often prescribed for these diagnoses. Today, over 700 different cannabis genotypes are being bred, and it is very important to describe in detail their cultivation, potential yields, chemical profile and stability, to be recommended to a particular patient with a specific diagnosis. The aim of this study was to evaluate the inflorescence yields and the content of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) of seven traditional genotypes of cannabis – Conspiracy Kush, Nurse Jackie, Jilly Bean, Nordle, Jack Cleaner 2, Jack Skellington and National Health Services. The plants were grown under controlled climatic conditions during six growing cycles at a density of 9 plants/m². Dried inflorescences from each plant were homogenized and analyzed by gas chromatography with flame ionization detection. The average yield per plant was 21.02 ± 3.33 g and the highest yields showed genotype Nurse Jackie (24.74 ± 6.11 g). The lowest yields were shown by genotype Jack Skellington (15.41 ± 4.02 g). Average Δ⁹-THC levels for each variety in all 6 growing cycles ranged from 15.69 ± 2.6 % to 19.31 ± 2.47 % (w/w). The lowest contents of Δ⁹-THC were measured in the Nordle genotype and the highest values were found in the Jack Cleaner 2 and Jack Skellington genotypes. Average CBD levels in the plants ranged from 0.45 ± 0.1 % to 0.57 ± 0.08 % (w/w) over six individual cycles. This study shows that among genotypes studied, the best parameters – high yield and stable cannabinoids production – are shown by genotypes Nurse Jackie and Jilly Bean.
... Cannabis sativa has been used as a medicine for centuries (see Hanus and Mechoulam, 2005;Iversen, 2008). It was not until the 1970's that oncologists demonstrated that smoked cannabis attenuated chemotherapy-induced nausea and vomiting (CINV). ...
Full-text available
Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic. If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea—a conditioned response to the contextual cues associated with illness-inducing chemotherapy—can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options. One of the first documented medicinal uses of Δ9-tetrahydrocannabinol (Δ9-THC) was for the treatment of chemotherapy-induced nausea and vomiting (CINV), and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating CINV. Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.
... The next metabolic step was shown to be the conversion of the allylic hydroxyl group into a carboxyl group (Scheme 5). The so formed THC- 7-oic acid was inactive (Mechoulam et al., 1973). It was shown to remain in the body as a glucoronide over many weeks. ...
The chemical research on the plant cannabinoids and their derivatives over two centuries is concisely reviewed. The tortuous path leading to the discovery of the endogenous cannabinoids is described. Future directions, which will probably be followed are delineated.
... The whole story about the isolation of cannabinoids from the plant was published in detail in [9]. Briefly, the main cannabinoids are cannabidiol, D 9 -tetrahydrocannabinol, and cannabinol. ...
Liquid – liquid extraction (LLE) processes have been widely applied to extract active pharmaceutical compounds (APCs) from plant materials at both the laboratory and industrial-scale. The approach to modify the aqueous phase with small molecule organic modifiers has been used to increase the solubility of APCs in the aqueous phase. This work investigates the solvent loss for 18 LLE systems, including three aqueous phase modifiers (methanol, ethanol and acetone), three traditional volatile organic compounds (VOCs) solvents (xylene, methyl isobutyl ketone (MIBK) and n-heptane) and three green solvents (d-limonene, α-pinene and p-cymene) with the aim of identifying the most suitable solvents for cannabinoid extraction from cannabis tissues. The solvent selection screening using COnductor-like Screening MOdel - Segment Activity Coefficient (COSMO-SAC) modelling was investigated. The loss of modifier into organic solvents generally increases as the original modifier concentration in aqueous solution increases. Methanol and ethanol are preferred for use in pharmaceutical LLE processes with volume fractions in organic phases at equilibrium of ≤ 0.02 v/v and ≤ 0.06 v/v, respectively. The organic solvent loss into the alcoholic aqueous phase at ≤ 0.8 v/v alcohol/water aqueous phase is negligible. MIBK and acetone are not suitable for pharmaceutical LLE processes with the presence of the modifier. Both Hanson solubility parameters (HSPs) and COSMO-SAC modelling show good agreement with the experimental outcomes.
The worldwide interest and push for the legalization of cannabis/marijuana, especially in the United States, are increasing with each passing day. The present article deals with the concise yet broad review of chemical, medicinal (neuroprotection), and adverse psychotic aspects of cannabis (marijuana or marihuana). The emphasis is made to understand the influence of tetrahydrocannabinol (THC) on a broad spectrum of properties ranging from psychosis, neuroprotection, neurotoxicity to medicinal. The reason why THC shows psychoactivity, but cannabidiol (CBD) does not, has been elucidated based on the minor difference in their chemical structures inhibiting CBD to bind with cannabinoid receptors due to steric hindrance. The distribution of cannabinoid receptors (namely, CB1 and CB2) in the human body and the role of endocannabinoids (namely, anandamide and 2-arachidonoyl glycerol) throughout the human system are described. The effect of the method of consumption (inhalation vs. ingestion) on the psychotropicity of cannabis/THC has also been discussed. Additionally, the effect of the use of synthetic endocannabinoid receptor blocker (antagonist) as a drug molecule for a specific purpose, such as for reducing the appetite, to treat obesity, or for the treatment of tobacco, alcohol, and other hard drugs induced addiction, and their potential adverse effects are also the focus of the article. Both the benefits and the risks of consuming cannabinoids are mainly dose-dependent, just like any other legal or prescription pharma products or regulated/unregulated psychotropic substances. Moderation is the right old prescription for a healthy and long productive life, and it applies to the use of medicinal, cultural, and/or recreational products like cannabis/cannabinoids. The traditional use of cannabis leaves (bhang) in India for medical as well as cultural purposes has been discussed from the modern scientific perspective. Lastly, the rapidly growing trend of the number of the publication of both the scientific research papers and the patent applications on cannabis, along with the market trend of cannabis-derived products, has been provided, showing quite high and promising growth.
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My thesis explores the role of the brain endocannabinoid system (ECS) in human sexuality and its potential in the management of hypoactive sexual desire disorder (HSDD). In the Foreword, I discuss history of cannabis use and outline the structural and functional basics of the ECS in the human brain and body and its possible involvement in mental and bodily diseases. Furthermore, I introduce the main argument of this thesis, which is the utilization of the ECS in the management of the HSDD. This section will also elucidate the main sources of inspiration which eventually led to an experimental research study carried out during the years of my doctoral candidacy. In the theoretical part of my thesis, in the Introduction section I discuss the concept of HSDD. In the next two chapters the available evidence from animal and human studies on the relationship between ECS and sexuality is covered. In the following chapter, I discuss potential mechanisms of sexual desire enhancing properties of the ECS. In the closing chapter of the theoretical part, I summarize the previous chapters including the knowledge gaps and outline the experimental part of my thesis. This part, in the form of commentaries, covers the specific research steps taken to support my main argument (sexual desire enhancing effect of the ECS agonization). Firstly, I comment on our study of pharmacokinetics of phytocannabinoids in the blood, regarding the dosage, specimen and frequency of use, as these might prove crucial in the clinical case management. In the second commentary, I introduce our experimental finding that ECS agonization might indeed lead to the heightened responsivity of hypothalamus and nucleus accumbens to visual erotica and that this could possibly be a consequence of modified dopaminergic transmission. Thirdly, I comment on our study, which examined brain functional connectivity and its time course during intoxication. This commentary sheds light on the heightened sensuousness as often observed during intoxication – another effect advantageous to sexual desire. In the last chapter of my thesis, I re-introduce my main argument, summarize our main findings and discuss the caveats and possible implementation strategies.
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In drug discovery programs, appropriate tuning of binding selectivity is a primary objective. Recently, considerable effort has been expended in elucidating the molecular mechanism of small molecules with potential interaction partners, such as proteins. Such work has elucidated the structural basis of selectivity among protein families or subtypes for which selectivity is considered to be difficult to gain. The continual challenge in drug development is the designing of a drug with appropriate selectivity and elucidating its molecular mechanism of selectivity for proteins such as G-protein coupled receptors (GPCRs) and kinases, which are difficult to crystallize and possess similar amino acid sequences of the catalytic domain and conformation. Thus, following the discovery of selective CB2 agonists and monopolar spindle 1 (Mps1) inhibitors, this work was aimed at elucidating the structural basis of their selectivity.
British scientists have played a leading role in the long history of cannabinoid and endocannabinoid research. Such research has progressed from the first crucial evaluation of the medicinal properties of Cannabis sativa in the Western world to pioneering studies of the chemical constituents of this plant, the development of in vitro biological assays to study cannabinoids, the identification of the mechanism of action of cannabinoids, the discovery of endocannabinoids and the assessment of their therapeutic implications. Stemming from the many innovative ideas and achievements of these researchers, I provide a personal view of where these studies have led us thus far and where they are likely to take us in the future.
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Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
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Two new cannabinoid acids were isolated from Cannabis sativa of Czechoslovak origin in the form of their derivates, by spectral analysis identified as Δ8 tetrahydrocannabinolic acid methylester and the other one of the formula C23H32O5 tentatively denoted as cannabioxoic acid, C22H30O5.
The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha,gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pK(i)=7.2) as well as very potent antagonistic activity (pA(2)=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.