Current Medicinal Chemistry, 2006, 13, 0000-0000 1
0929-8673/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.
Therapeutic Potential of Targeting the Endocannabinoids: Implications
for the Treatment of Obesity, Metabolic Syndrome, Drug Abuse and
S.A. Tucci*, J.C. Halford, J.A. Harrold and T.C. Kirkham
University of Liverpool, Eleanor Rathbone Building, Bedford Street South, Liverpool L69 7ZA, UK
Abstract: Rimonabant (SR141716, Acomplia®) has been described as an antagonist/inverse agonist at the cannabinoid re-
ceptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce
their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor.
It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of
either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained
from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits
in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disor-
ders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that ri-
monabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been
shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cy-
tokine tumour necrosis factor alpha (TNF?), thus indicating that CB1 receptor antagonists might exhibit potential anti-
inflammatory activity in acute and chronic diseases.
Keywords: Rimonabant/Acomplia/SR141716, obesity, appetite, clinical trials, addiction, metabolism, cannabinoids.
nabis sativa) for medicinal purposes date back over four
thousand years. However, the structures of the active can-
nabinoid compounds responsible for the plant’s pharmacol-
ogical properties were not identified until the latter half of
the last century . The cannabinoid ?9-tetrahydro-
cannabinol (THC) is considered to be the main chemical
component underlying the psychoactive properties of the
cannabis plant, which actually contains more than 60 bioac-
tive ingredients. Initially, the pharmacological actions of
plant-derived cannabinoids were thought to be due to disrup-
tive effects in the cell membrane. This argument was based
on the lipophilic nature of these compounds and the fact that
a specific binding site had not yet been identified. However,
twenty years after the discovery of THC, detailed structure-
activity relationship  and radioligand binding studies 
led to the notion that cannabinoid compounds worked
through signal transduction mechanisms comparable to those
defined for hormones and neurotransmitters, and that a cellu-
lar receptor was responsible for their effects rather than
membrane fluidity changes [4,5].
Historical references regarding the use of cannabis (Can-
nabinoid analogues led to the identification of specific bind-
ing sites that corresponded to two receptor types: the can-
nabinoid receptor type 1 (CB1), which was cloned from rat
and human brain cDNA libraries [6,7] and the cannabinoid
receptor type 2 (CB2), cloned from HL60 promyelocytic
cells . The pharmacological characterisation of those
The development of high-affinity, stereoselective can-
*Address correspondence to these authors at the University of Liverpool,
Eleanor Rathbone Building, Bedford Street South, Liverpool L69 7ZA, UK;
binding sites showed a strong correlation with the pharma-
cology of in vivo biological responses to cannabinoids [3,4].
brane receptors for plant-derived substances instigated the
search for an endogenous ligand. In 1992, Devane et al. 
characterised the first endogenous cannabinoid, which was
named anandamide (arachidonoyl ethanolamide, AEA) after
the Sanskrit word for “bliss”. Three years later, a second
endogenous cannabinoid, 2-arachidonoylglycerol (2-AG)
was simultaneously isolated from gut  and brain tissue
 (see Fig. 1). In 2001, the third cannabinoid in the series,
2-arachidonylglyceryl ether (noladin ether), was isolated
from porcine brain . In the following years, several other
related lipids with endocannabinoid properties, like vi-
rodhamine, have been identified but not yet fully character-
ised . The finding of endogenous substances that could
bind selectively to specific cannabinoid receptors thus led to
the revelation that there was a whole new endogenous sig-
nalling system, now known as the endogenous cannabinoid
system. This system comprises the cannabinoid receptors, all
the endogenous ligands (named endocannabinoids) and their
synthetic and inactivation mechanisms, and possibly other
molecular targets for the endocannabinoids such as some
voltage- and ligand- gated ion channels, transient potential
receptor-class channels, gap junctions, and neurotransmitter
The fact that mammalian cells displayed specific mem-
ised subtypes of cannabinoid receptors. CB1 is the predomi-
nant form expressed in the CNS. Of all known neurotrans-
mitter and hormone receptors, the CB1 receptor is by far the
most abundant in the mammalian brain . CB1 receptors
are also expressed, albeit at much lower levels, in the periph-
eral nervous system, as well as on the cells of the immune
system, in the heart, pancreas, liver, gastrointestinal, vascular
As previously mentioned, there are two fully character-
2 Current Medicinal Chemistry, 2006, Vol. 13, No. -- Tucci et al.
and adipose tissues and reproductive organs [18-28]. In the
central nervous system, CB1 receptors are expressed in re-
gions such as the hippocampus, cerebral cortex, some olfac-
tory regions, caudate, putamen, nucleus accumbens, that
influence a number of key functions including mood, motor
coordination, autonomic function, memory, sensation and
Fig. (1). Chemical structures of the plant derived cannabinoid, ?9
tetrahidrocanabinol (THC) and the endocannabinoids anandamide
and 2-arachydonylglycerol (2-AG).
reported to be more restricted, limited primarily to the im-
mune and haematopoietic cells . However, recent evi-
dence has shown CB2 receptors to be present within the
CNS, particularly cerebellar microglia [31,32]. Although still
controversial, Onaivi et al.  found CB2 gene transcript in
mice cerebellum and CB2 receptor like immunoreactivity has
been found in neuronal cells [34,35]. There is also growing
evidence of a wider distribution of CB2 in key organs such as
the pancreas  and adipose tissue . Additionally, CB1
and CB2 receptors can be co-expressed in some cells in
which cannabimimetic effects are mediated by their com-
bined activation .
The expression of the CB2 receptor had initially been
tors acting mainly through Gi/0-type G-proteins . Al-
though Gs coupling also appears to occur with the CB1 recep-
tor [39,40], the Gi/0 pathway seems to be the preferred one.
Both CB1 and CB2 receptors are G-protein coupled recep-
The major cannabinoid signalling pathways described so far
include the adenylyl cyclase inhibition , the inwardly
rectifying potassium channels  the voltage dependent
calcium channels , the Mitogen Activated Protein Kinase
(MAPK) cascade [44,45] and the phosphokinase B pathway
. Association of agonists with the CB1 receptor results in
GDP release and subsequent binding of GTP, resulting in the
dissociation of the ? subunit from the ?? dimer. The GTP-
bound ? subunit of Gi interacts with adenylyl cyclase, result-
ing in its inhibition. Hence, cannabimimetic compounds de-
crease cellular cAMP and shift protein kinase A target pro-
teins to the dephosphorylated state. The CB1 receptor has
also been shown to decrease Ca2+ currents in neurons, to
activate MAPK and focal adhesion kinase, and to induce
immediate early gene expression . There is evidence for
agonist selectivity for CB1 receptors coupled to different
subtypes of proteins . Cannabinoid receptor signal trans-
duction has recently been reviewed by Howlett 
fected cells, both CB1 [50-53] and CB2 receptors  have
been shown to have a high level of ligand-independent acti-
vation. (i.e., constitutive activity). It has been estimated that
up to 30% of CB1 receptors exist in the activated state while
70% are inactive .
In tissues naturally expressing CB1 receptors and in trans-
CB1 Receptor Antagonists
tors one of the most important G-protein-coupled receptor
(GPCR) targets for current drug discovery. A significant
milestone in cannabinoid
development of a diarylpyrazole derivative, rimonabant
(SR141716, Acomplia®), which shows selective antagonism
for the CB1 cannabinoid receptor, having over 1000-fold
selectivity over the CB2 subtype and non-cannabinoid
receptors and ion channels. Rimonabant was developed by
Sanofi Recherche in 1994  (see Fig. 2). It readily pre-
vents or reverses effects induced by agonist stimulation of
CB1 receptors, both in vivo and in vitro
Their therapeutic potential has made cannabinoid recep-
pharmacology was the
Fig. (2). Chemical structure of Rimonabant (SR141716).
nM [56,57]. Although rimonabant is CB1 selective, it is not
CB1 specific, since at higher concentrations (micromolar) it
can also interact with CB2 receptors [58-60] and stimulate
extracellular-signal-regulated protein kinase (ERK) . In
Rimonabant binds to the CB1 receptor with a Kd of 1–2
Therapeutic Potential of Targeting the Endocannabinoids Current Medicinal Chemistry, 2006, Vol. 13, No. -- 3
addition, at these concentrations rimonabant can both block
and activate the transient receptor potential vanilloid 1
(TRPV1) suggesting that it may be a TRPV1 receptor partial
agonist [16,62]. The drug may also block adenosine A1 re-
ceptors  and potassium and L-type calcium channels
the mechanisms by which cannabinoid agonists produce
their pharmacological effects and to elucidate the respective
physiological or pathophysiological roles of the CB1 receptor
and the endocannabinoids. The first evidence of the effects
of rimonabant came from an in vitro study where the drug
was able to antagonise the inhibitory effects of cannabinoid
receptor agonists on both mouse vas deferens contractions
and adenylyl cyclase activity in rat brain membranes [56,57].
Soon after, it was demonstrated that after intraperitoneal or
oral administration rimonabant was able to antagonise clas-
sical pharmacological and behavioural effects of cannabinoid
receptor agonists [56,66]. Apart from the antagonism of ex-
ogenously administered agonists, rimonabant exerts actions
when administered alone. Firstly, it was thought that these
effects originated from interference with the tonic actions of
the endogenous cannabinoids at the CB1 receptor, but it has
been demonstrated that in addition to the antagonism of the
endogenous cannabinoids, rimonabant also displays inverse
agonists properties . The inverse agonist properties of
rimonabant have been extensively reviewed in .
Rimonabant has been widely used as a tool to evaluate
ADDICTION AND WITHDRAWAL
cocaine elicit their effects by interacting with neural path-
ways in the brain . In particular, they share the common
property of activating mesolimbic dopamine systems, and
virtually all abused drugs elevate dopamine levels in the nu-
cleus accumbens [70-72]. Converging evidence indicates that
the endocannabinoid system is an important constituent of
the neural substrates involved in drug addiction. For in-
stance, cannabinoid CB1 receptors are expressed in the brain
reward circuitry and modulate the dopamine-releasing effects
of these drugs of abuse [17,73,74]. Moreover, CB1 and do-
pamine D2 receptors are co-localised (and form heterodi-
meric complexes) in the accumbens and mesolimbic dopa-
minergic neurones . Cannabinoids could also affect
mesolimbic dopamine by modulating activity in circuits
regulating dopamine neurons at the level of the ventral teg-
mental area (VTA). Human studies have shown that poly-
morphisms in components of the endocannabinoid system,
such as in the genes encoding the cannabinoid CB1 receptor
and the fatty acid amide hydrolase (FAAH) responsible for
endocannabinoid inactivation, are associated with substance
abuse and dependence [76,77].
Abused drugs such as alcohol, opiates, THC, nicotine and
logues in relation to drug addiction has been investigated
using validated experimental models of human drug seeking
and taking behaviours, such as drug self-administration
[78,79], and conditioned place preference , and by tech-
niques such as microdialysis to assess the neurochemical
correlates of these manipulations [81-83]. CB1 antagonist
administration has been shown to reduce the rewarding
and/or reinforcing properties of drugs of abuse, for example
by reducing heroin self-administration in opiate–dependent
The mechanism of action of rimonabant and its ana-
animals . Rimonabant seems to modulate dopamine ac-
tivity in a critical multi-synaptic neuronal circuit . For
instance, it appears to block the disinhibitory action of an
endocannabinoid tone on GABA-containing neurons. This
tone, which is insufficient to evoke dopamine release per se,
may play a permissive role on the ability of abused drugs to
evoke dopamine release in limbic terminal areas . Ri-
monabant might also block the modulatory action of endo-
cannabinoids on the excitatory glutamatergic input to the
GABA-containing neurons that project from the nucleus
accumbens to VTA and subserves a long-loop feedback .
This action may explain the effects of rimonabant on self-
administration of drugs which indirectly activate the
mesolimbic dopaminergic transmission, and its lack of effect
on self-administration of drugs that inhibit dopamine uptake
in terminal regions, such as cocaine [79,87,88]. Thus, the
endocannabinoid system may offer a novel target in the
treatment of drug addiction.
tween the neuropharmacological actions of cannabinoids and
cocaine, providing evidence that endocannabinoids might
play an important role in cocaine addiction. Despite the fact
that endocannabinoid transmission seems not to be involved
in the acute rewarding effects of cocaine , it seems to
play an important role in the neuronal processes underlying
cocaine-seeking behaviour. Rimonabant has been shown to
attenuate cocaine relapse induced by re-exposure to cocaine-
associated cues or cocaine itself . This may be especially
important in the treatment of cocaine abuse and dependence,
where no proven effective pharmacotherapy exists [91,92].
Cocaine: Many studies have shown commonalities be-
tion in drug use is of course marijuana. Due to the lack of
success in developing a rodent model of THC self-
administration , addiction to cannabinoids in rats has
been mainly studied using the drug discrimination model
. Animals can learn to reliably discriminate THC from
vehicle, and rimonabant produces reversible, dose-dependent
antagonism of the discriminative stimulus effects of THC in
rats and monkeys . Although not successful in rodents,
THC intravenous self-administration has been demonstrated
in squirrel monkeys . In this species, rimonabant is capa-
ble of almost entirely blocking the self-administration of
THC . In humans, rimonabant is also able to attenuate
subjective reinforcing effects induced by THC, albeit at high
doses . Administration of rimonabant to cannabinoid-
dependent animals precipitates a withdrawal syndrome (in
animals subjected to chronic treatment with extremely high
THC doses) that correlates with a reduction of dopamine
levels in the reward circuit [79,98]. These results suggest
that blockade of cannabinoid CB1 receptors may block both
the subjective and rewarding effects of marijuana.
THC: The most obvious target for rimonabant interven-
a link between the endogenous brain cannabinoid system and
the endogenous central opioid systems. Endogenous can-
nabinoids exert a facilitatory modulation of opioid reward
 and rimonabant pretreatment dose-dependently reduces
heroin self-administration . This evidence is further sup-
ported by studies that showed that CB1 and mu-opioid recep-
tor mRNAs are co-localized in brain areas linked to opiate
addiction and withdrawal, such as the nucleus accumbens,
septum, dorsal striatum, the central amygdaloid nucleus and
Opiates: There are several reports providing evidence of
4 Current Medicinal Chemistry, 2006, Vol. 13, No. -- Tucci et al.
the habenular complex . These results suggest that CB1
cannabinoid receptors may play a role in the neuroadaptive
processes associated with opiate dependence, and they lend
further support for the hypothesis of a potential role of can-
nabinoid receptors in the neurobiological changes that cul-
minate in drug addiction. Rimonabant has been able to in-
duce behavioural and endocrine alterations associated with
opiate withdrawal in dependent animals . Interestingly,
rimonabant does not seem to alter the heroin-associated in-
crease in nucleus accumbens dopamine, suggesting a non-
dopaminergic target in attenuating the rewarding effects of
the opiate . Rimonabant also attenuates reinstatement of
heroin self-administration in heroin-abstinent rats .
Moreover, long term administration of rimonabant has been
shown to partially ameliorate the naloxone-induced with-
drawal symptoms in morphine dependent rats, while having
no effect in the development of tolerance to morphine anal-
gesia . This finding suggests that rimonabant could be
used as a therapeutic tool in opiate addiction programs since
it is able to treat opiate withdrawal syndrome.
opioid  and endocannabinoid levels in brain reward
areas [103-105]. Cannabinoid agonists seem to enhance
ethanol intake [106,107], while antagonism at CB1 receptors
reduces consumption [87,108]. Several mechanisms have
been proposed to explain the reduction of ethanol intake
caused by cannabinoid antagonists. Blockade of CB1 recep-
tors could hinder the increase in opioid release induced by
ethanol . In addition, CB1 receptor antagonists also
seem to reduce the ethanol-induced increase in mesen-
cephalic dopamine neurones or block the disinhibition of
GABAergic neurons that, in turn activate dopamine neurons
. CB1 antagonism has been shown to reduce ethanol
intake in a wide variety of experimental paradigms: decreas-
ing voluntary ethanol consumption in rats and mice
[37,87,88,111]; blocking the acquisition of ethanol-drinking
behaviour, and decreasing the motivation to consume ethanol
in rats [106,112]. In addition to its ability to lessen the rein-
forcing properties of ethanol, rimonabant has also been able
to reduce ethanol seeking elicited by environmental condi-
tioning stimuli . As rimonabant influences the motiva-
tional and reinforcing properties of alcoholic beverages, it
may thus have potential as a drug for the treatment of alco-
hol addiction and craving [106,109,114].
Alcohol: Alcohol consumption is related to increases in
evidence involving the endocannabinoid system in some
effects of nicotine. The CB1 receptor plays a key role in this
interaction since CB1 knockout mice are less sensitive to the
motivational effects of nicotine , and rimonabant has
been shown to reduce nicotine self administration in rats
. Importantly, rimonabant has also been able to block the
responses to nicotine-associated cues, which play a very im-
portant role in sustaining smoking and reinstating smoking
after discontinuation . For instance, rimonabant reduces
the expression of a conditioned place preference to nicotine
. The interaction between the dopaminergic effects of
nicotine and rimonabant has been further investigated in
drug discrimination studies. The effects of rimonabant on
nicotine discriminative stimuli have shown that rimonabant
does not substitute for nicotine or block nicotine discrimina-
tive effects. Moreover, in rats trained to discriminate am-
phetamine from saline, rimonabant antagonises the substitu-
Nicotine: As with other addictive substances, there is
tion of nicotine for amphetamine. These findings, in addition
to showing that nicotine and amphetamine share a common
neuronal substrate, suggest that rimonabant selectively pre-
vents the dopaminergic effects of nicotine . So, rimona-
bant may not only reduce the motivational and reinforcing
effects of nicotine, but also diminish environmental cue-
induced nicotine craving and relapse. Preliminary results
from two large, multi-centre Phase III trials (STRATUS US
and Europe) show that smokers that received a high dose of
rimonabant had a higher percentage of quitting smoking
when compared to smokers that received the low dose or
placebo . Additionally, on average the subjects that
were given the higher dose of rimonabant also lost weight,
while those on the placebo gained about a kilogramme. In-
terestingly, the weight loss occurred predominantly among
patients who were overweight or obese. Patients of normal
weight did not lose weight during their treatment with ri-
ful tool in smoking cessation by attenuating the hyperactiva-
tion of the endocannabinoid system and the mesolimbic do-
paminergic neuronal pathway, and can thereby be differenti-
ated from substitutive treatments of nicotine addiction. Addi-
tionally, it has the advantage of reducing the likelihood of
weight gain that occurs when quitting smoking. More gener-
ally, in the past 10 years, the endocannabinoid system has
emerged as a potential regulator of motivational processes.
According to results obtained in animal models and human
studies, CB1 cannabinoid antagonists might be useful in
drugs of abuse addictions.
To summarize, rimonabant has the potential to be a use-
MEMORY AND LEARNING
2-AG are expressed at high levels in the hippocampus and
medial prefrontal cortex . Tonic activation of the can-
nabinoid system in these brain areas has been proposed to
play a role in an active forgetting process in which extrane-
ous information is deleted from memory storage [86,122].
This effect seems to be explained by the ability of CB1 re-
ceptor stimulation to reduce acetylcholine release in the me-
dial prefrontal cortex and hippocampus . On the other
hand, the blockade of CB1 receptors by cannabinoid receptor
antagonists such as rimonabant elevates the basal level of
acetylcholine in some brain areas. Thus, agonist stimulation
of CB1 receptors produce cognitive deficits, including mem-
ory impairment in humans as well as in laboratory animals
[124-127]. Therefore, it is possible that the blockade of CB1
receptors might be able to enhance cognitive processes in-
cluding memory retention. Cannabinoids may disrupt work-
ing memory through a CB1 receptor-dependent mechanism,
which suggests that the endocannabinoid system may have a
role in facilitating extinction and/or forgetting processes.
This hypothesis is supported by experiments in which ri-
monabant has been shown to enhance memory acquisition
assessed in a social recognition memory task , in a ra-
dial maze, a spatial memory task , and more recently, in
the inhibitory avoidance task . Conversely, rimonabant
has failed to enhance memory as assessed in fixed consecu-
tive number responding in pigeons , in an operant re-
peated acquisition procedure in rats , and in a non
match-to-position task in rats .
CB1 receptors and the endocannabinoids anandamide and
Therapeutic Potential of Targeting the Endocannabinoids Current Medicinal Chemistry, 2006, Vol. 13, No. -- 5
blocking cannabinoid transmission is more likely to enhance
memory that persists for minutes or hours than memory that
is prone to a rapid rate of forgetting, such as that found in
operant tasks. Additionally, rimonabant is able to improve
amnesia induced by ?-amyloid fragments in mice . All
this evidence indicates that it is imperative to explore the
potential of cannabinoid receptor antagonists as cognitive
enhancers, and to further evaluate whether their effects are
due to an antagonist or to an inverse agonist action at CB1
receptors. Although further study is needed, CB1 receptor
antagonists could become a new pharmacological alternative
in the treatment of pathophysiological states marked by
memory deficits, as in the case of traumatic brain injury or
neurodegenerative diseases, such as Alzheimer’s disease.
These behavioural studies taken together suggest that
trolling emotional behaviour and mood is poorly understood
. Although CB1 agonists have been reported to exert
anxiogenic actions [135-137], anxiolytic actions are com-
monly detected (and frequently reported by cannabis users)
[138,139]. The picture is even less clear with CB1 antago-
nists. While some studies have reported that rimonabant ex-
erts anxiolytic- or antidepressant-like effects [83,140-142],
others have found a lack of activity or even an anxiogenic-
like profile [136,143,144]. Nevertheless, it has been argued
that the majority of available evidence points towards an
anxiolytic effect of this compound . However, there is
the possibility that this action may be unrelated to blockade
of CB1 receptors, since the effect may be observed in both
wild type and CB1 knock-out mice [139,141].
The involvement of the endocannabinoid system in con-
phrenia through a number of lines of evidence; although,
again, its role in the aetiology and expression of psychosis is
not clear-cut. Giuffrida et al.  examined anandamide
levels in CSF of acute paranoid-type schizophrenic patients.
Anandamide levels were significantly elevated in antipsy-
chotic-naïve, first-episode paranoid schizophrenics when
compared to healthy controls. In unmedicated acute schizo-
phrenics, CSF anandamide was negatively correlated with
psychotic symptoms. Other studies have shown that chronic
antipsychotic administration can alter brain CB1 levels in
animal models. For example, an atypical antipsychotic, clo-
zapine, reduces cannabinoid binding in the nucleus accum-
bens . Such data, suggest that blockade of CB1 receptor
could be a good strategy to treat psychotic states. This idea is
supported by immunohistochemical and in vivo microdialy-
sis studies. Rimonabant selectively increases Fos- and neuro-
tensin-like immunoreactivity in mesocorticolimbic areas
, while leaving motor-related structures unaffected.
This pattern shows characteristics comparable to those re-
ported after administration of atypical neuroleptic drugs
. In vivo microdialysis studies have demonstrated that
rimonabant alters monoamine levels in several brain areas.
Rimonabant increases serotonin efflux in the medial prefron-
tal cortex and the nucleus accumbens. It also increases ace-
tylcholine, noradrenaline, dopamine and their metabolites in
the medial prefrontal cortex while having no effect on these
neurotransmitters in the nucleus accumbens . These
The endocannabinoid system has been linked to schizo-
changes are relevant to the positive, negative, and depressive
symptoms observed in psychotic states [148,149], and sug-
gest that the selectivity of rimonabant’s effects make this
compound a feasible candidate for the treatment of psycho-
in the regulation of ingestive behaviours. Plant-derived and
endogenous cannabinoids increase food intake in animals
and humans [150,151]. Therefore, it is clearly understand-
able that the antagonism of CB1 receptors should have an
effect on food intake. Indeed, a role for endocannabinoids in
feeding was largely conceived on the basis of the intake sup-
pressant actions of rimonabant, which were reported long
before any actions of the endogenous CB1 agonists on feed-
ing had been demonstrated . The first evidence of the
effect of rimonabant in the circuits that modulate appetite
came from the fact that rimonabant selectively inhibited su-
crose, food intake and ethanol drinking [87,108] without
disrupting any other behaviours.
The cannabinoid system has been shown to be involved
that rimonabant, when administered acute or chronically,
reliably suppressed intake in satiated and food deprived ani-
mals. These effects have been observed with systemic as
well as with central administration [88,153]. The effects of
rimonabant on food intake have also been investigated in
genetic models of obesity (ob/ob and Agouti yellow A(y)
mice and obese fa/fa rats), where it has shown to consistently
decrease food intake and body weight at a higher rate than
their lean counterparts [154,155].
After these initial observations, several studies showed
consumption, it is argued to be more effective in reducing
intake of palatable food. These findings led to the notion that
the endogenous cannabinoid system is involved in the modu-
lation of the reward value of food . Selective effects of
rimonabant in the modulation of reward is not restricted to
food, since, as previously discussed, it has an important role
in drug addiction. Therefore, a synergistic interaction be-
tween naloxone and rimonabant to suppress feeding, pro-
vides further evidence of important functional relationships
between endogenous cannabinoid and opioid systems, and
strengthens the postulated role for endocannabinoids in re-
ward processes contributing to the normal control of appetite
Although rimonabant is able to decrease overall food
food intake and consequently reduce body weight, led to the
investigation of its potential as an anti-obesity treatment.
This raised a great deal of interest on the effects on food in-
take and body weight after long-term administration. Several
studies performed in animal models showed that the decrease
in food intake elicited by chronic administration of rimona-
bant only lasted a few days (4-7 days). However, despite the
relatively short duration of the effects on food intake, the
suppression of body weight gain was maintained over the
full course of the treatment. This effect seems to be greater
in obese animals and reversible upon drug withdrawal .
In clinical trials, rimonabant has been shown to reduce food
intake, hunger and body weight in overweight and obese
men over 7 days of treatment . However, the effect of
rimonabant on human appetite (reducing hedonic value of
The fact that rimonabant possesses the ability to suppress
6 Current Medicinal Chemistry, 2006, Vol. 13, No. -- Tucci et al.
food, reducing its palatability or enhancing satiety) remains
to be fully characterised.
tolerance to the anorectic effect of rimonabant after repeated
administration is not fully understood. The differential
change in efficacy on food intake and body weight is pre-
sumably unrelated to metabolic tolerance, but it may also
reflect behavioural tolerance in response to persistent intake
suppression  or pharmacodynamic differences between
the central and peripheral cannabinoid systems. Rubino et al.
 proposed that desensitisation to the initial anorectic
effects of rimonabant may involve: uncoupling of the CB1
receptor from its transduction systems; homeostatic elevation
of endocannabinoid synthesis or tolerance to increased endo-
cannabinoid levels resulting from disinhibition of their nor-
mally negative control over specific neural pathways. Alter-
natively, the loss of anorectic potency may result from com-
pensatory upregulation of other orexigenic systems; a possi-
bility that may be supported by the rapid onset of rebound
weight gain seen in animal models and human trials after
rimonabant treatment is discontinued.
The mechanism underlying the rapid development of
anorectic effect of rimonabant results from an attenuation of
the rewarding properties of food, the contribution of drug-
induced aversion/malaise or induction of behaviours that are
incompatible with the expression of eating cannot be fully
excluded . Some studies have reported that at the doses
commonly used to suppress food intake, rimonabant pro-
motes behaviours that might interfere with feeding such as
wet-dog and head shakes, forepaw fluttering and facial rub-
bing [101,144]. Additionally, there is some evidence for the
possibility of rimonabant to induce conditioned taste aver-
sion (CTA) at anorectic doses which might partially account
for intake suppression .
Although the evidence supports the suggestion that the
METABOLIC EFFECTS IN WEIGHT LOSS
of rimonabant does not correlate with body weight loss,
which may suggest that in addition to its short-lived hy-
pophagic action, rimonabant may influence metabolic proc-
esses. Analysis of body composition in chronically-treated
animals showed that rimonabant significantly reduced adi-
pose stores, halving the proportion of body fat seen in con-
trols fed the same diet while preserving the lean mass. A
follow-up study confirmed these effects demonstrated that
the drug induced changes in body composition.
As discussed in the previous section the anorectic effect
is a plasma protein exclusively expressed and secreted by
adipose tissue. Adiponectin induces free fatty acid oxidation,
decrease hyperglycaemia and hyperinsulinemia and ulti-
mately reduces body weight [161-164]. In animals and hu-
mans, adiponectin expression in inversely proportional to
adiposity [165,166]. Rimonabant has been shown to be able
to induce overexpression of adiponectin mRNA and protein
in vitro and in vivo [167,168]. In addition, in adipose tissue
of CB1-receptor knockout mice, rimonabant had no effect on
adiponectin mRNA expression, demonstrating CB1 receptor
mediation. There is evidence that chronic rimonabant ad-
ministration increases adiponectin expression with greater
effects in obese animals . Moreover, when the effects
of rimonabant were assessed in “high risk” obese or over-
Adiponectin: adiponectin (previously known as ACRP30)
weight patients with dyslipidemia, it has been shown that the
drug significantly increased (amongst other biochemical
markers) adiponectin levels .
CB1 receptors are present in adipocytes [36,169]. CB1 activa-
tion has been shown to stimulate lipogenesis in adipocytes
. Moreover, CB1 have been shown to be up-regulated in
adipocytes derived from obese rodents . A recent study
has shown that rimonabant is able to inhibit the proliferation
and to delay maturation of cultured mouse pre-adipocytes. In
parallel to this inhibitory effect on pre-adipocyte cell prolif-
eration, rimonabant also stimulates mRNA expression and
protein levels of two late markers of adipocyte differentia-
tion (adiponectin and GAPDH) . This effect on pre-
adipocytes could be an additional mechanism of action of
rimonabant in the rimonabant -induced anti-obesity effects
and in particular the reduction of body fat mass. These re-
sults support the role of endocannabinoids in the develop-
ment and maintenance of obesity.
Adipocyte proliferation: It has been demonstrated that
anandamide levels in the liver . In turn, stimulation of
CB1 receptors in this organ exerts a lipogenic action; fatty
acid synthesis is increased by upregulation of the lipogenic
gene transcription factor sterol response element-binding
protein 1C (SREBP-1C) and its target enzymes acetyl-coA
carboxylase (ACC1) and fatty acid synthase (FAS). Rimona-
bant has been shown to be able to prevent these changes 
Fatty acid synthesis: Fat overconsumption increases
effect on energy expenditure suggesting that the anti-obesity
actions of rimonabant could be due, in part, to activation of
Thermogenesis: rimonabant also seems to have a direct
vious target for CB1 antagonist use is the treatment of over-
weight and obesity. A large body of evidence from animal
studies indicates the effectiveness of rimonabant in reducing
body weight and producing beneficial changes in the meta-
bolic correlates of obesity, this has led to the implementation
of clinical trials. Recent phase III clinical trials with rimona-
bant have indicated that the drug can effectively reduce
weight and adiposity in obese people (for a critical evalua-
tion of recently reported clinical data see  The first
peer-reviewed reports of Phase III trials (RIO-Europe and
RIO Lipids) have recently been published [168,174,175].
These reports shows that the rimonabant-treated group
achieved weight loss matching or exceeding the effects ob-
tained with earlier classes of appetite suppressants. Addi-
tionally, the metabolic effects of rimonabant seen in animal
models were replicated in the clinical trials. Interestingly, the
results obtained in these studies suggest that the improve-
ment in some metabolic risk factors (such as an increase in
high density lipoproteins, a decrease in plasma free fatty acid
levels and reduced insulin resistance) produced by rimona-
bant were far greater than could be attributed to weight loss
It can be seen from the studies reported here that an ob-
causes long-lasting hypotension and bradycardia . The
hypotension associated with several pathologies, such as
haemorrhage, endotoxemia, cardiogenic shock and advanced
liver cirrhosis, seems to be mediated, at least in part, by en-
Anandamide administration in most animal models
Therapeutic Potential of Targeting the Endocannabinoids Current Medicinal Chemistry, 2006, Vol. 13, No. -- 7
docannabinoids generated in monocytes, macrophages and
platelets . Rimonabant has been reported to inhibit or
reverse the hypotension associated with these pathologies.
[177-180]. In endotoxemic shock, LPS, a bacterial endo-
toxin, strongly stimulates the synthesis of anandamide in
macrophages [176,178]. There is evidence that indicates that
rimonabant inhibits the acute haemodynamic effects of LPS
by interacting with a cardiac receptor distinct from CB1 or
CB2 that mediates negative inotropy and may be activated by
anandamide or a related endocannabinoid released during
endotoxemia . These findings indicate that rimonabant
has additional peripheral sites of action that may also be of
therapeutic importance. The RIO Lipid study results showed
that rimonabant reduced blood pressure overall, but espe-
cially among patients with hypertension .
painful conditions. The possible mechanisms involved have
been the subject of many investigations. Although CB1 acti-
vation may be analgesic , several studies have impli-
cated the CB2 receptor in pain regulation. Specifically, CB2
agonists are analgesic in neuropathic pain models, peripheral
inflammatory models, and some sensitization models [183-
185]. However, rimonabant also seems to have some pain
modulating effects, although they have not been fully eluci-
dated. While acute administration of rimonabant in animal
models of chronic pain has demonstrated to be ineffective or
hyperalgesic, this drug appears to have beneficial effects
when administered chronically to animal models of neuro-
pathic pain . Rimonabant mediates its effect by several
mechanisms. In first place, it seems to inhibit the production
and release of chemical mediators, such as TNF?, cytokines,
nitric oxide (NO) and prostaglandins which play a key role
in the generation and maintenance of neuropathic hyperalge-
sia [187,188]. Additionally rimonabant favours myelin repair
and consequently promotes long-lasting functional recovery
. These findings suggest that rimonabant could be an
effective tool not only in alleviating neuropathic pain but
also in favouring the nerve myelin repair. In the light of the
current clinical need for neuropathic pain treatment, CB1
receptor antagonists could provide additional therapeutic
Cannabis and its extracts have long been used to treat
This activation could involve different signals associated
with CB1 receptor activation, like adenylyl cyclase , ion
channels , MAPK , and expression of the immedi-
ate-early gene Krox 24 . Moreover, in Chinese hamster
ovary cells transfected with the CB1 receptor, rimonabant
functions not only as an antagonist of CB1 receptors but also
as a selective inverse agonist for these receptors and delivers
a biological signal that blocks the Gi protein .
Rimonabant seems to modulate phagocyte activation.
indomethacin-induced intestinal injury . Indomethacin,
and other nonsteroidal anti-inflammatory agents, may
paradoxically cause intestinal damage in rats by local tissue
production and release of inflammatory cytokines and other
components of the inflammation cascade, such as
prostaglandins and nitric oxide [193,194]. The ability of ri-
monabant to prevent these type of injuries has been
Recently, it has been shown that rimonabant prevents
associated with a marked dose-related inhibition of tissue
TNF? levels and myeloperoxidase activity .
Additionally, rimonabant has been shown to inhibit intra-
cellular multiplication of certain bacteria such as B. suis in
human and murine macrophages . As previously men-
tioned, rimonabant is able to interact with macrophage CB1
receptors. From these observations it has been postulated
that rimonabant and other putative CB1 receptor could be
used as pharmacological tools to counteract intracellular
bacterial infections through the induction of macrophage
monabant could be used as potential anti-inflammatory and
anti-bacterial therapeutic agents in acute and chronic
diseases, such as intracellular bacterial infection, arthritis,
pulmonary inflammation and Crohn's disease, as well as
other pathologies in which inflammation and cytokines play
an important role.
The results obtained in these studies indicate that ri-
OTHER EFFECTS/ADVERSE EFFECTS
examination, especially in the light of its relevance to the
proposed future clinical use. This section will briefly enu-
merate some unrelated effects that have been reported with
the administration of rimonabant.
Rimonabant exerts other effects that still need further
multiple unrelated functions, it is plausible to expect several
unrelated effects of rimonabant to arise from antagonising
endogenous cannabinoid tone. From the clinical trials in-
volving rimonabant, the most frequently reported side-
effects are nausea, dizziness and diarrhea [174,196]. It has
also been reported to increase of intraocular pressure ,
intestinal motility and defecation ; and the enhance-
ment of arousal which leads to an increase in time spent in
As the endocannabinoid system seems to be involved in
ported to induce multiple sclerosis in one patient who re-
ceived the drug as a trial medication for obesity. This patient
had never had any neurological symptoms previous to the
treatment with the CB1 antagonist and interestingly, she re-
covered to near normal in the weeks after suspending the
rimonabant . There are several lines of evidence that
suggest that CB1 receptor agonists have both neuroprotective
 and immunosuppressive  effects. Therefore, it
would not seem implausible that CB1 antagonism may cause
CNS demyelination in susceptible subjects.
It is also worthy mentioning that rimonabant was re-
bant derivatives were reviewed by Barth and Rinaldi-
Carmona in 1999 . Since then, many papers describing
new derivatives have been published. Among these is
AM251, previously reported as a radio-imaging ligand for
the CB1 receptor . Recently, the anti-obesity effects of
AM251 were reported and are, not surprisingly, similar to
those of rimonabant [205-207].
The first structure-affinity relationships for the rimona-
been synthesized (reviewed in 196). One close analogue of
ethylpyrazole-3-piperidinecarboxamide (SR147778; surina-
To date, hundreds of diarylpyrazole derivatives have
8 Current Medicinal Chemistry, 2006, Vol. 13, No. -- Tucci et al.
bant)  possesses high affinity and selectivity for the
hCB1 cannabinoid receptor (see Fig. 3). This compound is
currently being investigated in clinical trials for the treatment
of obesity, as well as nicotine and alcohol addictions .
Another derivative, the 5-(4-bromophenyl)-1-(2,4-dichloro-
ide, was described in a very recent patent from Sanofi ,
and most major pharmaceutical companies are believed to be
undertaking parallel CB1 antagonist development pro-
have proved to be essential tools in the understanding of
cannabinoid pharmacology and biochemistry. The therapeu-
tic potential in the treatment of eating and movement disor-
ders, memory deficits, psychosis, and dependencies to vari-
ous addictive drugs has considerably increased the interest of
the pharmaceutical industry in these compounds (see Table
1). It is clear from the broad range of studies reviewed here,
Since their initial development, cannabinoid antagonists
Effects of Rimonabant on Addiction, Memory and Food Intake in Animal and Human Subjects
Species Test Effect Ref.
Adiction and withdrawal
Rats and mice Opioid self administration Reduction of self administration of heroin and morphine [78,84,210]
Squirrel monkeys Cannabinoid self administration Reduction of self administration 
Rats and mice
Reinstatement of opioid seeking behav-
Attenuation of reinstatement after exposure to drugs or cues. [84,210,212]
Rats Conditioned place preference to morphine Prevention of the development of conditioned place preference [80,213]
Rats and monkeys Cannabinoid drug discrimination Blockade of drug discrimination effects 
C57BL/6 mice Ethanol intake Blockade of ethanol drinking, ethanol seeking. 
Rats Nicotine consumption
Reduction of self-administration, blockade responses to associ-
Facilitated abstinence and reduction of weight gain associated
Memory and learning
Social recognition spatial memory inhibi-
tory avoidance tasks
Enhancement of memory acquisition [128-130]
Rats and pigeons
Fixed consecutive number responding,
operant repeated acquisition, non match-
No effect [131-133]
Appetite and food intake
Marmosets Intake of highly palatable food Reduction of intake 
Non obese adult rats Food intake/Body weight Weight reduction 
Non obese adult rats Intake of palatable food and bland chow Reduction of intake (both types of diets) 
Non obese adult rats Food intake Food intake reduction 
Newly born mouse pups Milk ingestion and growth Decrease of milk ingestion and growth, death 
Non obese adult rats
Microstructural analyses of licking for a
10% sucrose solution
Decrease of total number of licks 
Diet induced obese mice Food intake, body weight and adiposity
Transient reduction in food intake; suppression of body weight
Genetically obese rats Food intake and body weight
Decreased food intake and body weight gain – enhanced in
obese animals relative to lean heterozygotes
Non obese adult rats Opioid-induced feeding
Suppression of systemic and intra-PVN morphine induced feed-
Non obese adult rats
Intake of lab chow, high fat, high carbo-
Decreased intake of all diets 
Non obese adult rats Ghrelin induced food intake Blockade of ghrelin hyperphagia 
CB1 knockout and wild-
Dose dependently decreased food intake in wild type mice, but
not knock outs.
Non obese adult rats
Responses for food under a second order
Body weight, obesity-related metabolic
and cardiovascular risk factors
Reduced pellet consumption and instrumental responding dur-
ing the appetitive and consummatory phases
Obese humans weight loss, improvement of metabolic indexes
CB1 knockout and wild-
Progressive ratio schedule using fat and
Attenuation of the reinforcing effects of fat and sweet food 
Therapeutic Potential of Targeting the Endocannabinoids Current Medicinal Chemistry, 2006, Vol. 13, No. -- 9
that antagonists/inverse agonists of the cannabinoid receptors
represent one of the most active areas of current pharmaceu-
tical development, from which should emerge some promis-
ing new therapeutic tools.
Surinabant (SR 147778)
Fig. (3). Chemical structure of Surinabant (SR147778).
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Received: February 10, 2006
Revised: June 12, 2006 Accepted: June 13, 2006