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An analogue of (-)-cannabidiol, O-2654 (604) has recently been disclosed as a high-affinity CB1 antagonist ligand [350]. Compound (604) was found to be significantly more potent (Ki = 114 nM) than cannabidiol (Ki = 4.9 mM) in the displacement of tritium-labelled CP 55,940 in mouse brain tissues. The value obtained for (604), while less potent than that reported for (382) (1.98-12.3 nM), is comparable with the early Lilly antagonist LY320135 (Ki = 141 nM) [351]. In addition, (604) was found to antagonise WIN 55,2122 by competing with the agonist for the CB1 receptors. Unlike (382), the cannabidiol analogue is thought to behave as a neutral antagonist.

A recent patent application from Roche [352] described a 2-amino-benzothiazole series. Roche claimed that compound (605) exhibited an IC50 value of 0.73 mM at CBi, and showed in excess of 10-fold selectivity over the CB2 receptor. The compounds were described as being of potential use in the treatment of a range of diseases, including CNS and psychiatric disorders, type-2 diabetes, gastrointestinal diseases, cardiovascular disorders, infertility disorders, inflammation, cancer, atherosclerosis, cerebral vascular incidents and cranial trauma.

A series of 12 tetrahydroquinoline compounds, functioning as antagonists or inverse agonists of the CB1 receptor, has been disclosed [353]. The requisite three hydrophobic groups, in the example (606), three unsubstituted phenyl groups are present, as is an adjacent hydrogen-bond acceptor (either the 2-oxo group of the central heterocycle, or the sulfonamide oxygen). A sulfonamide moiety was also present in a patent application, which at the time of writing is the most recent disclosure from Merck and Co. [354]. Again, a branched butyl chain forms the backbone from which two aryl groups are appended (607). CB1 functional activity for the compounds was claimed to be lower than 1 mM while the CB2 functional activity was reported to be higher than 1 mM.



Our current understanding of the potential therapeutic applications of CB1 antagonists owes a great deal to the discovery of rimonabant (382). Indeed, clinical data demonstrating the efficacy of (382) in the treatment of obesity and nicotine addiction has provided a substantial driving force for the expanding research effort into this approach.

The increase in appetite resulting from cannabis use has long been recognised and has also been observed in animals that have been administered cannabinoid agonists [355]. The endocannabinoid system also appears to play a key role in the regulation of appetite [356]. Endocannabinoid levels in the limbic forebrain have been shown to increase with food deprivation, while 2-AG levels in the hypothalamus reduce during feeding [357]. Anand-amide (1) administration into the ventromedial hypothalamus has also been shown to stimulate appetite in rats [358]. The hypothalamus uses leptin as the primary signal to modulate food intake and energy balance and there is evidence linking leptin and endocannabinoids in the regulation of food intake [359]. Di Marzo and co-workers associated defective leptin signalling with elevated hypothalamic levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats, cerebellar endocannabinoid levels were not affected. Acute leptin treatment of normal rats and ob/ob mice reduced (1) and 2-AG levels in the hypothalamus.

In additon to the central role of endocannabinoids in the regulation of feeding behaviour, a peripheral role has also been described. Gomez and co-workers [360] reported that food deprivation produced a 7-fold reduction in (1) levels in the small intestine of rats, but not in the brain or stomach. Intestinal (1) levels returned to normal when feeding resumed. The authors also showed that peripheral, but not central administration of (382) reduced food intake. The endocannabinoid system has also been reported to regulate peripheral lipogenesis [361].

The role of the endocannabinoids and exogenously administered agonists outlined above led to an interest in testing the effects of selective CB1 receptor antagonists on feeding behaviour [261, 362, 363]. Rimonabant (382) and SR147778 (385) have been shown to reduce food intake and weight gain in ordinary rats without altering water intake [270, 364-366]. Rimonabant (382) has also been shown to cause a transient decrease in food intake accompanied by a sustained decrease in bodyweight and adiposity in dietary-induced obese mice [367]. Leptin, insulin and glucose levels were all normalised in these mice following (382) treatment, together with an increase in serum adiponectin levels [367, 368]. While (382) did not modify HDL-cholesterol and had modest effects on total cholesterol, it significantly reduced triglycerides and LDL-cholesterol and increased the HDL/LDL-cholesterol ratio.

CB1 knock-out mice exhibit resistance to dietary-induced obesity in terms of food intake, weight gain, body fat composition and the development of dietary-induced insulin resistance [369]. The effects of (382) on feeding behaviour and body weight are not observed in these animals, confirming that these are mediated through the CB1 receptor [359, 367]. CB1 knock-out mice do not demonstrate a decrease in food intake under free feeding conditions, but food intake is reduced following food deprivation.

Clinical trials with (382) have provided the most exciting evidence for the utility of CB1 antagonists in the treatment of obesity, results of the Rimonabant in Obesity (RIO)-Europe trial having been published very recently [370, 371]. In this trial, 1,507 patients with body-mass index of 30kg/m2 or greater, or body-mass index greater than 27 kg/m2 with treated or untreated dyslipidaemia, hypertension or both, were randomised to receive doubleblind treatment with placebo, 5mg (382) or 20 mg (382) once daily in addition to a mild hypocaloric diet (600 kcal/day deficit). The primary efficacy endpoint was weight change from baseline after 1-year treatment in the intention-to-treat population. Weight loss at 1 year was significantly greater in patients treated with (382) 5mg (mean —3.4 kg) and 20 mg (—6.6 kg) compared to placebo (—1.8 kg). Significantly more patients treated with (382) 20 mg than placebo achieved weight loss of 5% or greater (50.9% versus 19.2%) and 10% or greater (27.4% versus 7.3%). Rimonabant (382), 20 mg, produced significantly greater improvements than placebo in waist circumference, HDL-cholesterol, triglycerides, insulin resistance and prevalence of metabolic syndrome. The effects of (382) 5 mg were of less significance. (382) was generally well tolerated with mild and transient side effects including nausea, dizziness, diarrhoea and vomiting.

Rimonabant (382) has also shown promise in pre-clinical and clinical studies as an aid to smoking cessation. (382) decreases nicotine self-administration in rats and nicotine-induced dopamine release in nucleus acumbens [372], and also reversed nicotine-seeking behaviour in rats several weeks after nicotine withdrawal [373]. In a 10-week, placebo-controlled trial, (382) was shown to prolong abstinence rates from tobacco during the final 4 weeks of the treatment period [370]. Furthermore, while patients in placebo groups in several studies gained weight, (382) patients lost weight or experienced less weight gain than those on placebo. Weight gain following nicotine withdrawal is a major factor in reducing abstinence rates. In addition to their utility as aids to smoking cessation, CB1 receptor antagonists have shown potential pre-clinically in the treatment of addiction to other substances including morphine, heroin and alcohol [374-377].

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTS1 antagonist. Haloperidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CB1 antagonism is not appropriate in the treatment of this condition.

Pre-clinical data support the potential application of CB1 antagonists in the treatment of various other conditions. These include memory disorders [379], sexual dysfunction [380], neuro-inflammation [381] and asthma [382].

cb2 receptor antagonists

CB2 receptor antagonists have received much less attention than their CB1 counterparts, with only a relatively small number of compounds available and less clarity on their potential therapeutic role. A selection of the available compounds that have been shown to act as antagonists of the CB2 receptor and their suggested utilities will be covered in this section.

As observed in the CB1 antagonist section, pyrazole derivatives again form an important class of antagonists for the CB2 receptor. A structural analogue of rimonabant (382), SR144528 (608), is a potent CB2 antagonist/ inverse agonist identified by Sanofi [383]. This compound has proved to be a useful tool in determining the function of CB2 receptors. The compound has subnanomolar affinity for CB2 receptors with 700-fold selectivity over CB1 receptors. Following oral administration, (608) totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes without interacting with CB1 receptors in the brain.

Conformationally restricted pyrazole-derived CB2 selective antagonists were described in a patent application from Sanofi-Synthelabo [384]. Compounds included in the application, exemplified by compound (609) are claimed to act as antagonists at CB2 receptors (K;<5 x 10_7M) with selectivity of at least 10-fold over CB1 receptors.

Moving away from pyrazole-derived compounds, an aminoalkyl-indole, AM630 (610), acts as a CB2 receptor antagonist/inverse agonist with a CB2 K value of 31.2nM and 165-fold selectivity over the CB1 receptor subtype [385]. It is interesting to note that this compound has been shown to act as a low-affinity partial agonist, antagonist or inverse agonist at CB1 receptors [6].

Iwamura and Ueda [386] described compound (611) as a CB2 selective inverse agonist in a patent application. The potential therapeutic roles of CB2 antagonists are not clearly defined at the moment, although roles in regulation of the immune system and inflammation have been widely proposed. This patent application describes that activity of compound (611) in a mouse model of asthma, in which the compound suppressed immediate and late-phase asthmatic response and airway hyper-responsiveness.

(608) SR144528

(608) SR144528

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