新型减肥药利莫那班的研究进展

利莫那班是一种大麻素1型受体（CB1）拮抗剂,能明显降低食欲、减轻体重,近年来常用于治疗肥胖症。本文简要介绍了利莫那班的物理化学性质、合成、减肥作用机制以及不良反应,详细阐述了利莫那班检测技术的研究进展。     

大麻素受体1阻断剂在治疗代谢综合征中的作用

代谢综合征(MS)是严重危害人类健康的一类疾病,其中肥胖是MS发生发展的核心环节,研究证实大麻素受体(CBR)1与其密切相关。CBR1是G蛋白偶联受体家族的成员,其基因及蛋白结构已经明确。近来发现CBR1阻断剂可通过中枢神经系统和外周组织两方面作用机制减轻体重、改善代谢,同时对戒烟有帮助;其中利莫那班目前已进入Ⅲ期临床研究,经证实其可有效减轻体重,无明显不良反应。CBR1阻断剂可望为防治MS提供新途径。     

大麻素受体1阻断剂在治疗肥胖症中的作用

肥胖症已成为世界范围内的流行病，严重危害着人类健康。目前研究已经证实大麻素受体1（cannabinoid receptorl，CB1-R）与其发生发展有着密切的关系。CB1-R属于G蛋白偶联受体，其分布和基因结构已经明确。近年来发现CB1-R阻断剂能通过中枢和外周两种途经降低体重，调节能量代谢过程，同时还对乙醇、香烟及药物成瘾有帮助；目前利莫那班（rimonabant，SR141716）已经进入Ⅲ期临床试验，能有效地降低体重，且无明显不良反应。CB1-R阻断剂有望为肥胖症的治疗带来新的曙光。     

基于PPARs信号通路探索CB1对脂质代谢的调节作用

目的 研究CB1对PPARs信号通路在高脂饮食诱导肥胖小鼠脂质代谢的调节作用.方法 构建小鼠肥胖模型,观察给予CB1抑制剂利莫那班后小鼠体重、肝脏重量及血清生化指标的变化,并检测CB1、PPARα、PPAR β和PPARγ基因在各组织mRNA水平的表达情况.结果 利莫那班降低了小鼠的体重和肝脏重量(P＜ 0.05);改善了血清生化指标(P＜0.05);各组织中CB1基因mRNA水平的表达降低(P＜ 0.05);PPARα、PPARγ基因在皮下脂肪、内脏脂肪、肝脏组织mRNA水平的表达显著增高(P＜ 0.05);PPAR 3基因在各组织mRNA水平表达情况差异无统计学意义.结论 CB1通过作用于PPARα、PPARγ调节脂质代谢,为临床上脂质代谢紊乱的治疗提供了另一个可靠的理论依据.     

肥胖症治疗新药——利莫纳班

利莫纳班是选择性的大麻素CB1受体阻滞药,具有抑制进食、减轻体重、帮助戒烟、改善血脂代谢和糖代谢等作用。利莫纳班治疗肥胖研究等表明利莫纳班可用于减肥、戒烟、预防代谢综合征等。     

利莫纳班增加抑郁风险

一种新型减肥药利莫纳班(rimonabant,商品名:Acomplia)由于存在精神系统不良反应,被欧洲药品管理局(EMEA)禁用于重度抑郁症(major depression)或使用抗抑郁药治疗的患者。利莫纳班由法国赛诺菲-安万特公司近年研制开发,其作用机制与先前的减肥药完全不同,它是一种大麻素CB1受体拮抗剂,通过选择性地阻断大麻素与CB1受体结合,降低内源性大麻系统活性,来调节食物摄入、能量储存和消耗。从临床效果看,利莫纳班是迄今发现的最好的减轻体重的药物。研究表明它能有效降低糖化血红蛋白、甘油三酯和非高密度脂蛋白胆固醇,升高高密度脂蛋白胆固醇…     

大麻CB_2受体在中枢神经系统的分布及其激动剂的药理作用

大麻受体分为大麻受体1(CB1)和大麻受体2(CB2),CB2受体主要分布于外周免疫系统,目前研究发现其在中枢神经系统(CNS)也有少量的分布,这可能与其中枢作用密切相关。已有文献报道CB2受体激动剂具有抑制疼痛产生和持续及神经退行性病变等药理学特性,且长期给药不产生明显的精神和躯体依赖等副作用,显示出良好的临床应用前景。为了更好地认识、研究和利用CB2受体及其激动剂,该文综述了CB2受体在CNS的分布及其药理作用特点。     

降糖降脂新药—利莫纳班

萨诺菲·安万特(Sanofi-Aventis)公司的rimonabant(Acomplia,利莫纳班,药品剂量规格20 mg·d-1)获欧洲委员会(EC)批准,于2006年7月在全部25个欧盟成员国上市,用于存在多种心脏代谢风险因素如2型糖尿病或脂质代谢失调的肥胖或超重病人饮食和运动疗法的辅助治疗。它是选择性CB1阻滞剂。CB1受体存在于对葡萄糖和脂质代谢至关重要的大脑和外周组织(包括脂肪组织、肝脏、胃肠道和肌肉)内。CB1受体阻滞剂的作用是减弱类大麻类系统的过度活动,这是一个在调剂体重和控制能量平衡以及葡萄糖和脂质代谢方面起重要作用的生理系统。批准的依据是对…     

选择性1型大麻素受体阻滞剂利莫那班

利莫那班是选择性大麻素受体1（CBR1）阻滞剂，在对肥胖、戒烟以及代谢综合征治疗中具有良好作用，是惟一用于临床控制食欲和降低体重的内源性大麻素受体阻滞剂。现对其药理作用以及临床评价做一综述。     

大麻素受体与肝病

内源性大麻素系统(the endocannabinoid system,ECS)包括大麻素受体、内源性大麻素及参与生物合成、降解的酶,主要分布于脑部,在外周组织也有分布,包括肝脏。肝脏各种疾病其ECS均可被激活。肝硬化时血管及心脏的CB1受体激活后引起血管舒张及心肌病,CB1受体受阻后,上述作用可受抑制;肝纤维化小鼠模型中,肝星状细胞CB1被激活可引起肝纤维化,CB1受体受阻则可减缓肝纤维化的进展;因高脂饮食或长期饮酒引起的脂肪肝也依赖于外周CB1的激活,包括肝脏CB1受体,同时CB1受体会引起胰岛素抵抗及血脂异常。虽然CB1受体拮抗剂因其精神神经方面的副作用使其临床应用受到限制,但如果能将其副作用限制则有望用于临床。     

Is the cannabinoid CB1 receptor antagonist rimonabant advancing the treatment of obesity?

Orlistat and sibutramine are the most commonly used drugs in the reduction of body weight, but both of these result in only modest weight reduction. In diet-induced obesity of the mouse, the cannabinoid CB1 receptor antagonist rimonabant induced a marked, sustained reduction of body weight and obesity. In the first major clinical trial (Rimonabant in Obesity), patients were put on a hypocaloric diet, which lead to weight loss of 3.6 kg after 1 year. This weight loss was increased to 8.6 kg by treatment with rimonabant 20 mg/day for the year. Discontinuations due to nausea, vomiting, diarrhoea and headache were more common in the rimonabant 20 mg/day group than the placebo group, but occurred in very few patients. Rimonabant is an addition to the available drugs for the treatment of obesity.     

Cannabinoid receptor antagonists and obesity

The cannabinoid-1 (CB1) receptor plays a role in the regulation of appetitive behavior. Exogenously administered cannabinoid receptor agonists stimulate food consumption in animals and humans. Endogenous cannabinoid receptor agonists are present in the brain, and the brain level of these agonists increases with greater demand of food by rodents. Specific CB1 receptor antagonist compounds have been discovered that display high affinity and selectivity for the CB1 receptor. CB1 receptor antagonists inhibit both acute and long-term food intake in rodents. Chronic treatment with CB1 antagonists results in a sustained reduction in body weight in rodents (5 weeks), and weight loss in humans (16 weeks). Patent literature indicates CB1 receptor antagonist discovery efforts at a number of pharmaceutical companies. The CB1 receptor antagonist, rimonabant (SR-141716), discovered by Sanofi-Synthélabo, is in phase III clinical trials for the treatment of obesity and has been found to decrease appetite and body weight in humans.     

Cannabinoids and the regulation of ingestive behaviour

Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.     

Will the new CB1 cannabinoid receptor antagonist SR-147778 have advantages over rimonabant?

Obesity and alcoholism are two common modern-day diseases. The cannabinoid CB1 receptor antagonist rimonabant is in Phase III clinical trial for the treatment of obesity with preliminary results showing that it decreases appetite and body weight. Animal studies have shown that rimonabant is effective in the treatment of alcoholism. SR-147778 is a new potent and selective CB1 receptor antagonist. In animals, SR-147778 has been shown to inhibit CB1 receptor-mediated hypothermia, analgesia and slowing of gastro-intestinal transit. In rats trained to drink sucrose, the oral administration of SR-147778 3 mg/kg, before the presentation of sucrose, decreased the consumption of sucrose. SR-147778 3mg/kg also reduced spontaneous feeding in rats deprived of food and also in non-deprived rats. In Sardinian alcohol--preferring (sP) rats, in the alcohol-naive state, SR-147778 slowed the development of a preference for alcohol. In alcohol-experienced sP rats SR-147778 (2.5, 5 and 10 mg/kg p.o.) reduced the alcohol intake. When alcohol-experienced sP rats are deprived of alcohol for 15 days, there is a large intake of alcohol on reintroduction of alcohol, and this response was almost abolished by treatment with SR-147778. From the preclinical studies published to date, there is no obvious major point of difference between rimonabant and SR-147778, and both are promising agents for the treatmentof obesity and alcoholism.     

CB(1) receptor antagonism: biological basis for metabolic effects

The endocannabinoid system (ECS) is a complex physiologic system that affects metabolic pathways. A dysregulated ECS has been demonstrated in animal models of obesity and the expression of the cannabinoid type 1 (CB(1)) receptor in both brain and peripheral tissues suggests that selective antagonism at this receptor could target multiple tissues involved in metabolic homeostasis. In clinical trials with obese patients, treatment with the CB(1) receptor antagonist rimonabant was associated with clinically meaningful weight loss, as well as improved serum lipids and glycemic control. The biological basis for the metabolic effects of rimonabant (SR141716) appears to involve the modulation of metabolism through antagonism at a single receptor with several target organs.     

Therapeutic potential of targeting the endocannabinoids: implications for the treatment of obesity, metabolic syndrome, drug abuse and smoking cessation

Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor 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 disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant 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 cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.     

Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight

The endocannabinoid system consists of lipid-derived agonists that activate cannabinoid (CB) receptors. CB receptor agonists, namely, the phytocannabinoid Δ(9)-THC and the endocannabinoid anandamide, increase hunger sensation and food intake. These discoveries led to the clinical use of Δ(9)-THC derivatives for the treatment of cancer and HIV-related nausea and cachexia. Animal studies clarified the important role of CB1 receptors in the hypothalamus and in the limbic system in mediating orexigenic effects. In parallel, data on CB1-specific blockade either by drugs or by genetic ablation further demonstrated that CB1 inhibition protects against weight gain induced by high-fat feeding and reduces body weight in obese animals and humans. The mechanisms of weight reduction by CB1 blockade are complex: they comprise interactions with several orexigenic and anorexigenic neuropeptides and hormones, regulation of sympathetic activity, influences on mitochondrial function, and on lipogenesis. Although these mechanisms appear to be mainly mediated by the CNS, weight loss also occurs when drugs that do not reach CNS concentrations sufficient to inhibit CB1 signaling are used. The development of peripherally restricted CB1 inverse agonists and antagonists opened new routes in CB1 pharmacology because centrally acting CB1 inverse agonists, e.g., rimonabant and taranabant, exerted unacceptable side effects that precluded their further development and application as weight loss drugs. Tissue and circulating endocannabinoid concentrations are often increased in animal models of obesity and in obese humans, especially those with visceral fat accumulation. Thus, further research on CB1 inhibition is still promising to treat human obesity.     

CB1 cannabinoid antagonists: structure-activity relationships and potential therapeutic applications

During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.