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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
Introduction
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
21
H
26
O
2
. 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
23
In a systematic study of the antibacterial substances in hemp Krejcˇí and
S
ˇ
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 (
9
-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,
8
-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
9
-THC acids, A
and B [24, 25], as well as
8
-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
9
-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 (
8
-THC and
8
-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
1
).
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
9
-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
2
) 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
CB
1
cannabinoid receptor (K
i
= 21.2 ± 0.5 nM) and causes sedation, hypother-
mia, intestinal immobility and mild antinociception in mice. It binds very
weakly to the CB
2
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
1
(K
i
= 250 ± 130 nM) than the CB
2
receptor
[5052].
One of the typical endocannabinoid effects is pain suppression. Some
endogenous fatty acid derivatives (palmitoylethanolamide, oleamide), which
do not bind to CB
1
or CB
2
, 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]. [
3
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
8
-THC, 11-hydroxy-
8
-THC,
led to the highly active ligand 11-hydroxy-
8
-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
D
value
of 45 pM, and is the most potent CB
1
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
1
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 [
3
H](R)-(+)-WIN-55212-2.
The first potent and selective antagonist of the central cannabinoid receptor
(CB
1
), SR-141716A, was reported in 1994 by a group at Sanofi [76]. This
compound is not active on the peripheral cannabinoid receptor (CB
2
) and has
rapidly become a new tool in the study of cannabinoid receptor mechanisms
and in research on new therapeutic agents. Another novel CB
1
antagonist,
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
2
), SR-144528 [78], and like the
above-mentioned CB
1
antagonist, it soon became a major tool in cannabinoid
research [79].
Our group reported the preparation of a CB
2
-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
1
receptor. In HU-308 both phenolic groups
are blocked as methyl ethers. This is in contrast to cannabinoid CB
1
agonists
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
1
/CB
2
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
i
value of 20 ± 1.6 nM for
the CB
1
receptor [87]. The K
i
value for binding to the CB
2
receptor from
mouse spleen is 815 nM [88]. Thus (R)-methanandamide has a high selectivi-
ty for the CB
1
receptor.
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
guanosine-5'-O-(3-[
35
S]thio)triphosphate ([
35
S]GTPγS) binding in mouse
brain membrane preparations [91].
Gatley et al. [92] have developed a novel radioligand, [
123
I]AM-281, struc-
turally related to the CB
1
-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
2
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
2
receptor in a mouse spleen preparation (K
i
= 3.4 ± 0.5 nM), with good selectiv-
ity versus the CB
1
receptor in a rat brain preparation (K
i
= 280 ± 41 nM). This
compound has recently been found to inhibit neuropathic pain in rodents [93].
AM-2233, a novel aminoalkylindole CB
1
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
1
receptor. AM-2233 represents the first agonist CB1 recep-
tor ligand (K
i
= 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
1
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
2
) 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
2
-binding affinities. Four compounds showed very high
selectivity for the CB
2
receptor.
Cannabinoid structureactivity relationship data have indicated that the
cannabinoid side chain and the phenolic hydroxyl are key elements in CB
1
receptor recognition. To test this hypothesis, the 1-deoxy analog, JWH-051, of
the very potent cannabinoid 11-hydroxy-
8
-THC-dimethylheptyl (HU-210)
was prepared and the affinity of this compound for the CB
1
receptor was deter-
mined [100]. Contrary to expectations, this 1-deoxy analog still had high affin-
ity for the CB
1
receptor (K
i
= 1.2 ± 0.1 nM) and even greater affinity for the
Cannabinoid chemistry: an overview 33
Structure 10
CB
2
receptor (K
i
= 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
2
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-
8
-THC analogues
[101]. Five of these analogues had high affinity (K
i
20 nM) for the CB
2
receptor. Four of them also had low affinity for the CB
1
receptor (K
i
295 nM).
3-(1',1'-Dimethylbutyl)-1-deoxy-
8
-THC (JWH-133) had very high affinity
for the CB
2
receptor (K
i
= 3.4 ± 1.0 nM) and low affinity for the CB
1
receptor
(K
i
= 677 ± 132 nM).
In view of the importance of the CB
2
receptor, three series of CB
2
-selective
cannabinoid receptor ligands, 1-methoxy-, 1-deoxy-11-hydroxy- and
11-hydroxy-1-methoxy-
8
-THCs, were designed [102]. All of these com-
pounds have greater affinity for the CB
2
receptor than for the CB
1
receptor;
however, only 1-methoxy-3-(1',1'-dimethylhexyl)-
8
-THC (JWH-229) had
essentially no affinity for the CB
1
receptor (K
i
= 3134 ± 110 nM) with high
affinity for CB
2
(K
i
= 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
1
receptor was described [103]. These com-
pounds were found to be CB
1
antagonists. SLV319 was found to be a potent
CB
1
antagonist (K
i
= 7.8 nM) close to that of the Sanofi compound
SR-141716A, with more than 1000-fold selectivity against CB
2
.
Additional synthetic compounds that bind to the CB
1
and/or CB
2
receptors
have been mentioned in patents. These were recently reviewed by Hertzog
[104].
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
1
(K
i
= 34 nM) and CB
2
(K
i
= 11 nM). The patent applica-
tion refers to the compound as having CB
2
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
2
over CB
1
. Compound 2,for
instance, exhibited K
i
values of 2.28 and 0.309 nM for the CB
1
and CB
2
recep-
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
1
receptor.
A series of aromatic CB
2
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
2
with a K
i
value in the range 0.110 nM.
Researchers at AstraZeneca have disclosed a series of benzimidazoles and
azabenzimidazoles to be CB
2
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
2
(K
i
= 3.1 nM) with much greater affinity
than to CB
1
(K
i
= 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
2
receptor. For instance, compound 5 binds to CB
2
with a
K
i
value of 0.8 nM and to CB
1
with a K
i
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
2
agonists useful for the treatment
of pain, inflammation and autoimmune diseases [111]. Binding data for the
compounds to CB
1
and CB
2
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
i
values of 40 and 0.8 nM, respectively, for the CB
1
and CB
2
receptors. In addition, this compound was assessed by intravenous
administration and exhibited ED
50
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
2
agonists [112]. Compound 7 is reported to be a potent CB
2
agonist (K
i
= 19 nM) with 88-fold selectivity for the CB
2
over the CB
1
receptor.
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
2
agonists,
of which compounds 8 and 9 are examples [113, 114]. Selectivity data for sev-
eral of the compounds with regard to CB
2
/CB
1
affinities are described. For
38 L.O. Hanusˇ and R. Mechoulam
Structure 19
Structure 20
Structure 21
example, compound 8 binds to CB
2
with a K
i
value of 0.3 nM and a K
i
value
of >5000 nM for CB
1
. Compound 9 displayed a K
i
value of 1.2 nM at the CB
2
receptor and 80 nM at the CB
1
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
2
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
2
receptor with a K
i
value of 4 nM,
with very little affinity for CB
1
(K
i
< 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
2
receptor than for the CB
1
recep-
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
2
selectivity (CB
1
,
K
i
= 1 µM; CB
2,
K
i
= 25 ± 1.8 nM).
Indole derivatives were prepared and tested for their CB
1
and CB
2
receptor
affinities [117]. Three new highly selective CB
2
receptor agonists were identi-
fied, namely JWH-120 (CB
1
, K
i
= 1054 ± 31 nM; CB
2
, K
i
= 6.1 ± 0.7 nM),
JWH-151 (CB
1
, K
i
>10000 nM; CB
2
, K
i
= 30 ± 1.1 nM) and JWH-267 (CB
1
,
K
i
= 381 ± 16 nM; CB
2
, K
i
= 7.2 ± 0.14 nM).
Cannabinoid chemistry: an overview 39
Structure 22
Structure 23
Conclusions
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
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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. ...
Thesis
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). ...
Article
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). ...
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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. ...
Article
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. ...
Article
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.
Chapter
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.
Thesis
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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.
Thesis
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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.
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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.
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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.