Invited review
Prospective therapeutic agents for obesity: Molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists

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Highlights

  • Role of CB1 receptor in obesity is discussed.

  • Centrally and peripherally acting CB1 receptor antagonists are reviewed.

  • There is need to design peripherally acting selective CB1 receptor antagonists.

  • Molecular modelling studies are also incorporated.

  • Development strategies of selective CB1 receptor antagonists are discussed.

Abstract

Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review.

Graphical abstract

Diaryl as well as non-diaryl heterocyclic rings substituted at different positions have been designed and evaluated as centrally and peripherally active CB1 receptor antagonist as potential therapeutic agents for the control of obesity.

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Introduction

According to World Health Organization (WHO), overweight and obesity are defined as abnormal or excessive fat accumulation in body that may impair health. More than1.4 billion adults in the age of 20 and older were overweight in 2008, among which more than 200 million were men and nearly 300 million women were found to be obese. A very jiggered fact is that more than 40 million children under the age of five were obese in 2011. At present, obesity has become the fifth leading risk factor for global deaths [1]. Obesity creates a major risk factor for a number of diseases like cardiovascular diseases, type 2 diabetes, osteoarthritis, hypertension, stroke, sleep apnea, and certain types of cancers [2], [3] indicating that obesity is one of the major challenging health problems these days [4].

Worldwide, researchers are searching for newer targets for the treatment of obesity. Till date various targets have been identified and unfortunately none have provided a potential therapy for obesity. Hence, there is a worldwide demand to develop a “magic bullet” to lose body weight [5]. For the treatment of obesity, peptide targets like cholecystokinin (CCK-1) agonists, glucagon-like peptide 1 (GLP-1) analogs, amylin analogs, neuropeptide Y agonists, peptide YY agonists, ghrelin antagonists, MCH1 receptor antagonists, MC4 receptor agonists and monoamine targets such as 5-HT2B receptor agonists, 5-HT6 receptor antagonists, 5-HT2C agonists, β3 AR agonists, dopamine agonists as well as lipase inhibitors, anticonvulsants, cannabinoid 1 (CB1) receptor antagonists, μ-opioid receptor antagonists, sympathomimetic agents, AgRP (agouti-related protein) inhibitors, MetAP2 (methionine aminopeptidase) inhibitors mixed noradrenaline/serotonin reuptake inhibitors, mixed dopamine and noradrenaline reuptake inhibitors and mixed noradrenaline dopamine and serotonin reuptake inhibitors have been identified [6]. Phentermine, a sympathomimetic amine was approved for short-term use by FDA in 1959 as an anti-obesity agent [7]. But phentermine was withdrawn from Europe market due to its risk of cardiovascular effects and abuse potential [6]. Lorcaserin is a selective 5-HT2C receptor agonist. It was initially rejected in 2010 due to carcinogenicity observed in preclinical studies, but on re-filing FDA approved lorcaserin in July 2012. A CB1 receptor antagonist, rimonabant was withdrawn from the market in 2008 due to its psychiatric side effects [8]. Orlistat, a gastrointestinal and pancreatic lipase inhibitor acting peripherally was the first long-term use drug approved by FDA for the treatment of obesity in 1999 and is available in the market. It does not show any clinically significant effects on triglycerides or HDL cholesterol. It exhibited gastrointestinal adverse effects like flatulence, steatorrhoea, malabsorbtion, faecal urgency, faecal incontinence, abdominal pain, upset stomach, dyspepsia and reduced absorption of fat soluble vitamins [9], [10], [11]. Researchers have begun to develop combination therapy for the treatment of obesity. This strategy was adopted due to the fact that various mechanisms are involved in food intake modulation. It has also been proposed that more favourable weight loss and a better safety profile can be achieved by using multiple targeting agents [7]. Qnexa is a combination of topiramate (anticonvulsant) and phentermine (amphetamine derivative) which has completed phase III clinical trial although FDA did not approve Qnexa in its current form in 2010. The FDA had asked for its data regarding teratogenicity in 2011, Qnexa was approved in 2012 [7] after ensuring its safety. Contrave, another drug, is a combination of naltrexone (opioid antagonist) and bupropion (antidepressant). FDA's Endocrinologic and Metabolic Drug Advisory Committee voted to support Contrave for approval in 2010. But in 2011, the FDA asked for its data regarding long-term cardiovascular risk assessment [7]. Sibutramine a NA/5-HT reuptake inhibitor was withdrawn from market due to its increased risk of cardiovascular side effects in 2010 [8]. Current status of all these anti-obesity agents is shown in Table 1. Thus, it is clear that the choice of available drugs for the treatment of obesity is highly limited. Hence, there is an urgent need to develop effective anti-obesity drugs [12].

Although rimonabant has been withdrawn from the market and several other CB1 receptor antagonists have been also terminated from development programmes, it can be said that researchers have not yet reached the altar of development of CB1 receptor antagonists for the treatment of obesity [8]. Brain non-penetrant CB1 receptor antagonists that act only at peripheral site might prove as promising therapeutics for obesity [13]. Along with this, two new intriguing suggestions are also in consideration. The first suggestion is based on low-dose combination of rimonabant with other anorectic agents such as opioid receptor antagonists, 5-HT2C receptor agonists or gut peptide CCK-8s. The second one is related to recent genomic studies which state that development of anxiety or depression in response to agents like rimonabant may be contributed by variants (polymorphisms) of the CB1 receptor gene alone or in combination with the gene for serotonin transporter (SLC6A4) [8]. Thus, a lot of work still remains to be done for the design and optimization of existing lead molecules of CB1 receptor antagonists. Discussion on centrally acting selective CB1 receptor antagonists is equally important for the development of peripherally acting selective CB1 receptor antagonists. Hence, in this review we have discussed all the developments that have taken place in the field by considering both centrally and peripherally acting selective CB1 receptor antagonists which have been reported till date.

The endocannabinoids belong to the biologically active lipid family which bind and activate cannabinoid receptors [14]. Anandamide and 2-arachidonyl-sn-glycerol (2-AG) are the two main endocannabinoids or endogenous agonists acting as neurotransmitters or neuromodulators [10], [14], [15]. Both these endocannabinoids are derived from arachidonic acid and released from a variety of different types of cells. They are metabolised or inactivated immediately after performing their function by the enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAG lipase), as shown in Fig. 1 [6], [10], [16]. The functions of these endocannabinoids are related to food intake and control of energy balance including peripheral and central orexigenics. They are present in the hypothalamus region which is responsible for controlling food intake. When these endocannabinoids are released in the hypothalamic nucleus, they stimulate food intake [10]. Peripheral lipid and glucose metabolism may also be regulated by endocannabinoids after binding to CB1 receptors that are present in the peripheral tissues such as white adipose tissue, liver, skeletal muscles and pancreas [17]. Thus, over-activation of endocannabinoid system or increased endocannabinoid levels cause obesity [9], [18]. Blocking the overactivity of endocannabinoids in the peripheral tissues by antagonising the CB1 receptor can control obesity. Thus, there is a focus on CB1 receptor antagonists as a new class of drugs for the treatment of obesity [19], [20].

For more than 4000 years, cannabis from Cannabis sativa has been utilized for psycho stimulant purposes due to its mind-altering effect, as well as for therapeutic purposes [21]. The cannabis plant contains more than 60 cannabinoids but Δ9-tetrahydrocannabinol (THC) is the most active and clinically relevant psychoactive component identified in 1974. Synthetic THC like dronabinol is used in the treatment of post-chemotheraphy nausea and emesis, and also in anorexia associated with HIV infection [22]. After the discovery of THC, extensive researches have been investigated to find its specific receptors known as CB1 and CB2 receptor [4]. Data suggest that there may be a third CB3 receptor also but it has yet to be cloned [23], [24]. The CB1 receptor was cloned in 1990 [25] and later in 1993 CB2 receptor was also cloned. The CB1 receptor is located mainly in brain areas including basal ganglia, cerebellum, hippocampus and cortex, and in peripheral tissues such as testis, eye, urinary bladder, ileum, adipose tissue, liver, skeletal muscles and pancreas. On the other hand, the CB2 receptor is almost exclusively expressed in cells of the immune system in peripheral tissues, the thymus, tonsils, bone marrow, spleen, pancreas, peripheral nerve terminals, microglial cells, glioma and skin tumour cells as shown in Fig. 2 [26], [27], [28], [29], [30].

Both CB1 and CB2 receptors contain seven transmembrane (TM) domains which are connected by three intracellular and three extracellular loops as I1, I2, I3 and E1, E2, E3 respectively. The intracellular C-terminus region starts with a small helical domain and contains a site of palmitoylation. The extracellular N-terminus contains potential N-glycosylation site as shown in Fig. 3. The ligand binding pocket is present in the crevice that is formed by the helix bundle. It has been suggested through site directed mutation and crystal structures of rhodopsin and the β1/2-adrenergic receptors that ligand binding occurs with the residues present in the TM3-5-6-7. But, the mutation of lysine 192 present in TM3 of the CB1 receptor proved critical for the binding of some agonists such as CP55940, HU-210 and anandamide while no effect was observed with WIN55212 which indicated that the binding site was not exactly the same for binding to various ligands. CB receptors do not form a disulfide bond between TM2 and E2 unlike other class A GPCRs, although CB receptors contain two cysteine residues in E2 which can form a disulfide bridge. A 44% amino acid sequence identity exists between CB1 and CB2 receptors encoded by different genes [4].

Both CB1 and CB2 receptors are G-protein-coupled receptors (GPCR) belong to the rhodopsin GPCR family (Class A). Both excitatory and inhibitory neurotransmissions present in most of the brain region are inhibited by the activation of CB1 receptors present on the nerve terminals [31]. In peripheral tissues and neurons, activation of CB1 receptors inhibits adenylate cyclase which decreases the production of cAMP, causing attenuation of the protein kinase A (PKA) signalling cascade [31], [32], [33]. PKA phosphorylates the potassium channel protein in the absence of cannabinoids resulting in decreased outward potassium current. But in the presence of cannabinoids, reduction in the phosphorylation of the potassium channel occurs resulting increased outward potassium current [34]. Phosphorylation is regulated by CB1 receptors and activation of CB1 receptors result in stimulation of different members of mitogen activated protein kinase family (MAPks) including extracelluar signal-regulated kinase-1 and -2 (ERK 1/2), p38 MAPK and c-jun N-terminal kinase (JNK) [32], [35]. Stimulation of CB1 receptors in neurons inhibit voltage-activated Ca2+ channels directly and mediate retrograde signal transduction and activate G-protein coupled ‘inwardly-rectifying K+ channels’ which decrease neuronal excitability [31], [36], [37]. CB1 receptor mediated downstream signalling and intracellular protein machinery is shown in Fig. 4 [37]. CB2 receptors have an almost similar mechanism of action as CB1 receptors in inhibiting adenylyl cyclase and decreasing the production of cAMP in different types of cells. Stimulation of CB2 receptors also activate MAPK cascades. But CB2 receptors do not act on ion channels [34], [38], [39].

It has been well recognised that endocannabinoid system (ECS) and especially CB1 receptor have a vital role in energy homeostasis and modulate both food intake and fat metabolism [40]. The endogenous signalling system in ECS acts on both central as well as peripheral sites. Recent investigations have indicated that the ECS activity is increased in human obesity [41], [42], [43], [44]. In the central site, food intake is controlled by the ECS, mainly at two functional levels i.e. the hypothalamus and the limbic systems. The role of hypothalamic ECS is to modulate feeding by decreasing satiety signals and increasing orexigenic signals [45]. After fasting for a short time, the ECS in the hypothalamus becomes activated, stimulating the appetite subsequently [46]. Endocannabinoids are shown to increase eating incitement, possibly reinforcing the incentive and hedonic value of food. The limbic system also plays a part in controlling over intake of food [45], [47]. Stimulation of CB1 receptors on the GABAergic terminals in the Ventral Tegmental Area (VTA) increases dopaminergic neuronal activity resulting in increased release of dopamine in the nucleus accumbens [48]. Release of dopamine in the mesolimbic pathway increases the consumption of food. Thus, it has become clear by the growing evidence that the interaction between mesolimbic endocannabinoid and dopamine systems regulate food intake. In peripheral sites, ECS regulates energy balance by peripheral lipogenic mechanism and modulation of lipid and carbohydrate metabolism. It is proposed on the basis of available evidence that activation of CB1 receptors in the peripheral tissue boosts the lipogenesis, lipid storage, insulin secretion, glucagon secretion and adiponectin modulation [45], [47]. Stimulation of CB1 receptors in adipocytes, increases synthesis and storage of triglycerides, decreases adiponectin and facilitates glucose uptake which leads to obesity [49]. Leptin level is decreased due to blocking of CB1 receptors resulting in increase in food intake [50]. Conversely, leptin administration decreases the levels of endocannabinoids in the hypothalamus [51]. Along with this, stimulation of CB1 receptors leads to activation of lipoprotein lipase and enhances the sequestering of free fatty acids by adipocytes. Hence, blocking of CB1 receptors in adipose tissue decreases free fatty acid concentration into the circulation which results in lowering of fat storage and improved insulin sensitivity [41], [46], [49], [52], [53], [54], [55]. In the GI tract, the endocannabinoids acting on CB1 receptors reduce the satiety signals generated by cholescystokinin [56]. This CB1 agonism also enhances the ability of ghrelin to stimulate food intake [57]. It has also been reported that inhibition or mutations in the endocannabinoid metabolizing enzyme FAAH, increases the endocannabinoid levels thus accentuating the orexigenic and lipogenic actions of these agents [43]. Activation of CB1 receptors in intestine produces slow peristalsis and prolonged intestinal transit times which may promote weight gain. Therefore, blocking of CB1 receptors produces a pro-kinetic effect [46]. Hepatic CB1 receptors have a vital role in lipogenesis. Activation of CB1 receptors in liver stimulates several lipogenic factors such as sterol response element-binding protein-1C (SREBP-1C), which increases fatty acid synthesis resulting in the development of fatty liver [58], [59], [60]. Glucose metabolism and insulin sensitivity is also controlled by ECS [61]. Hence, blocking of CB1 receptors in skeletal muscles enhances basal oxygen consumption and glucose uptake, resulting in increase in energy expenditure and improvement in insulin sensitivity. Peripheral CB1 receptors therefore have a prominent role in the modulation of metabolism [45], [46], [47]. The role of ECS in central and peripheral systems is shown in Fig. 5 [46]. Reducing ECS activity by CB1 receptor antagonists results in decrease in food intake and increased energy expenditure [62]. Thus, development of CB1 receptor antagonists could be a promising strategy in the treatment of obesity.

Selectivity is a very critical part in the designing of CB1 receptor antagonists. Two types of selectivity must be seen in CB1 receptor antagonists. First selectivity is related to CB1 over CB2 receptors. Agonists of the CB2 receptors have been shown to possess cardioprotective effects which are mediated through attenuation of TNF-α and endothelial inflammatory mediators. Thus, it may be speculated that blockade of these receptors may worsen cardiometabolic conditions like myocardial infarction and/or atherosclerosis [63], [64]. Blockade of CB2 receptors reduced apoptosis of peritoneal macrophages induced by oxLDL thus accentuating foam cell formation [65]. Additionally, CB2 receptor activation has been shown to exhibit immunosuppressive actions. Blockade of these receptors can lead to worsening of autoimmune disorders like colitis [66]. CB2−/− mice showed enhanced cisplatin-induced kidney inflammation, oxidation/nitrosative stress, cell death and dysfunction in the renal capsule; effects which might have been shown upon treatment with CB2 receptor antagonists [67]. In rodents, CB2 receptor antagonists increased dermal thickness and leucocyte infiltration in the skin leading to a fibrosis like condition [68], [69]. CB2−/− mice have been reported to have a condition similar to post-menopausal osteoporosis which could be attributed to the decreased inhibition of osteoclast activity [70]. In light of these findings, it would be prudent to design agents which avoided CB2 receptor antagonism.

Second selectivity aspect is concerned with peripherally acting over centrally acting CB1 receptor antagonists. Centrally acting CB1 receptor antagonists exhibited psychiatric side effects like depression, anxiety, irritability or even suicidal tendency as well as gastrointestinal disorders like nausea and neurological alterations like headaches and vertigo [10]. Hence, compounds should be designed keeping the fact in mind that the designed compounds should not cross the blood brain barrier (BBB) and should act only peripherally.

Using of molecular modelling techniques, McAllister et al. [71] reported the binding region for CB1 receptor. The transmembrane helix (TMH) 3-4-5-6 of cannabinoid receptor formed aromatic domain which contained F3.25, F3.36, W4.64, Y5.39, W5.43 and W6.48 residues. Selective CB1 receptor antagonist, rimonabant and CB1/CB2 receptor agonist WIN55212-2 both were bound within this microdomain as shown in Fig. 6. Rimonabant exhibited direct aromatic stacking interactions with F3.36, Y5.39 and W5.43 residues as well as hydrogen bonding with K3.28. In a similar microdomain, WIN55212-2 also showed direct aromatic stacking interactions with F3.36, W5.43 and W6.48 residues. Mutation in F3.36 produced 3-fold loss in affinity for rimonabant and 9-fold loss in affinity for WIN55212-2 indicating that F3.36 had direct interactions with rimonabant and WIN55212-2. The W5.43 mutation showed 8-fold loss in affinity for WIN55212-2 and deleterious effect upon rimonabant binding. The obtained results supported the modelling studies that W5.43 oriented centrally in the aromatic cluster interaction with rimonabant. The model suggested that W5.43 had direct stacking interactions with both monocholophenyl and dichlorophenyl rings of rimonabant. W5.43 also helps rimonabant to orient in the binding pocket. Mutation in W6.48 showed 4-fold and 7-fold loss in affinity for WIN55212-2 and rimonabant respectively. W6.48 does not interact directly with rimonabant but interact through F3.36. It has become clear by the mutation studies that F3.36, W5.43, and W6.48 are part of the binding pocket for both rimonabant and WIN55212-2. Along with this, it was also observed that mutation in K3.28 resulted in 17-fold loss in binding affinity for rimonabant but the binding affinity and receptor activity for WIN55212-2 was retained. This indicates that K3.28 is one of the key residues which directly interacts with rimonabant by forming hydrogen bond but it does not interact with WIN55212-2 [72], [73].

As far as binding region of CB2 receptor is concerned, Leu108, Ser112, Pro168, Leu169, Trp194 and Trp258 residues present in TMH 3-4-5 formed the active site for CB2 receptor. Selectivity for CB2 receptor is mainly produced by the interaction of S3.31 and F5.46 residues present in CB2. It has been observed that the selectivity for CB2 receptor was increased when a lipophilic group of the ligand interacted with F5.46 and another group was capable of forming a hydrogen bond with S3.31 [74], [75], [76]. Thus, molecular modelling studies can help in the designing of newer selective CB1 receptor antagonists.

Designing of CB1 receptor antagonists showing selectivity towards CB1 receptors over CB2 receptors as well as selectivity for peripheral sites over central action is of prime importance. Hence, peripherally acting selective CB1 receptor antagonists could act as a safe strategy for the treatment of obesity.

In the late 1980's, the structure of THC was modified for the first time to develop a selective CB1 receptor antagonist, but the results obtained were disappointing [77]. After long research efforts, Rinaldi-Carmona and co-workers from Sanofi Recherche finally discovered rimonabant (1, Fig. 7) in 1994. Rimonabant was the first potent CB1 receptor antagonist having 1000 fold CB1 selectivity over CB2 [78]. In 2006, Rimonabant was approved by European Commission as an anti-obesity agent. Unfortunately, European Medicine Agency had to withdraw the drug from the market due to the risk posed by the drug like serious psychiatric disorders including drug induced suicidal tendency. Still rimonabant was considered as the most promising lead compound in the treatment of obesity [77]. Taranabant (2, Fig. 7) was developed by Merck Research Laboratory as a CB1-inverse agonist for the treatment of obesity due to its anorectic effect [79]. But the compound was suspended in phase III clinical development programme for the same reasons of psychiatric problems. Other compounds like surinabant [80] (3, Fig. 7) and otenabant [81] (4, Fig. 7) were also terminated in phase III development programme [77]. Solvay Pharmaceuticals Research Laboratories discovered ibipinabant (5, Fig. 7) as a CB1 receptor antagonist [82].

Recently, TM38837 (6, Fig. 7) was discovered by 7TM Pharma as a peripherally acting CB1 receptor antagonist devoid of CNS penetration and showing brain plasma ratio of 1:33 [83]. At 100 mg dose, TM38837 does not cross BBB thus causing no effect on CNS [84]. AM6545 (7, Fig. 7) was developed as a peripheral neutral antagonist [85], [86]. Neutral antagonists were designed with the assumption that such compounds would be devoid of or have decreased psychiatric and other side effects while retaining their metabolic action [9]. Compound 7 was a rimonabant derivative exhibiting very promising properties with more convincing evidence for peripherally effective selective CB1 receptor antagonism. Compound 7 had a marked ability to improve glucose tolerance, caused increased adiponectin levels, lowered leptin and insulin levels and caused reduction in triglycerides [61]. Thus, designing of neutral CB1 receptor antagonists was considered to be a safer and effective strategy for the treatment of obesity [87].

Researchers at present are focussing on the development of peripherally acting CB1 receptor antagonists for minimization or prevention of CNS adverse effects [9]. Generally, polar compounds are poor brain entrants while increasing lipophilicity enhances brain penetration [88]. Thus, peripheral acting CB1 receptor antagonists can be designed by increasing polar surface area (PSA) and lowering the lipophilicity. Neutral compounds have also been developed as peripherally acting CB1 receptor antagonists devoid of adverse effects showing little or no brain penetration [87], [89], [90]. Some charged compounds have also been developed because charged moieties do not cross BBB. Thus, at present designing of peripherally acting CB1 receptor antagonists is the prime task which could be proved as a potential target for the treatment of obesity. Till date various reviews [91], [92], [93], [94], [95], [96], [97], [98] covering the development of compounds acting on CB1 and/or CB2 receptors are reported along with some patented compounds [99], [100], [101], [102]. In this article, various chemical modification strategies and computational studies used in the direction of development of selective CB1 receptor antagonists are focussed upon.

Section snippets

Development of CB1 receptor antagonists

As rimonabant was the first compound to be recognized as a CB1 receptor antagonist for the treatment of obesity, most of the structural modifications have been done on the basic scaffold of 1,5-diaryl pyrazole of rimonabant with substituents at different positions on the basic scaffold. The pyrazole ring has been replaced with different five and six membered rings and also by bicyclic or tricyclic ring systems. Diaryl rings of rimonabant have been eliminated in some cases to design selective

Molecular modelling studies in the designing of CB1 receptor antagonists

Now days, molecular modelling has become an integral part of drug design and development process. Here, the molecular modelling studies of cannabinoid receptor antagonists is incorporated for better understanding of ligand receptor interactions as well as for further development or designing of selective CB1 receptor antagonists. Molecular modelling studies have been carried out by various groups for the designing and optimization of CB1 receptor antagonists. Ligand based designing tools like

Conclusions

Being a multifactorial health problem there is no effective therapy available currently for the treatment of obesity. CB1 receptor antagonists may prove to be promising therapeutics and one such antagonist rimonabant (1) acting centrally was introduced in the market as an anti-obesity drug in 2006 but unfortunately due to some psychiatric side effects it was withdrawn in 2008. Other centrally acting molecules such as taranabant (2), surinabant (3) and otenabant (4) have also been withdrawn from

Acknowledgement

MKS is thankful to University Grants Commission, New Delhi for the award of Junior Research Fellowships under the RFSMS-BSR programme [No. F. 7-129/2007 (BSR)].

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