Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine<sub>2C</sub> Agonist: in Vitro and in Vivo Pharmacological Characterization

Thomsen, William J.; Grottick, Andrew J.; Menzaghi, Frederique; Reyes-Saldana, Hazel; Espitia, Stephen; Yuskin, Diane; Whelan, Kevin; Martin, Michael M.; Morgan, Michael; Chen, Weichao; Al-Shamma, Hussien; Smith, Brian M.; Chalmers, Derek; Behan, Dominic P.

doi:10.1124/jpet.107.133348

Cited by 375 publications

(341 citation statements)

References 49 publications

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“…Maximum care was given in order to avoid stress during the oral supplementation of vitamin D 3 . Rats underwent 14 d of treatment, so that they were habituated to vitamin D 3 supplementation (14,15) . The last dose of vitamin D 3 and insulin was given 24 h before killing to minimise stressinduced endocrine changes due to oral administration.…”

Section: Methodsmentioning

confidence: 99%

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

George¹,

Kumar

Antony

et al. 2012

Br J Nutr

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Diabetes mellitus is a growing health problem worldwide and is associated with severe liver complications. The aim of the present study is to analyse the status of metabolic and free-radical-scavenging enzymes and second messengers in the liver of streptozotocin (STZ)-induced diabetic rats, and to determine the hepatoprotective role of vitamin D 3 . All studies were performed using the liver of adult male Wistar rats. Gene expression studies were carried out using real-time PCR with specific probes. Second messenger levels were determined using 3 H-labelled Biotrak assay kits, and glucose uptake assay with D-[ 14 C]glucose. The present results show that there was a decrease in hepatic glucose uptake, malate dehydrogenase activity, glycogen content, inositol triphosphate (IP 3 ) and cyclic GMP levels, and superoxide dismutase, glutathione peroxidase, phospholipase C, cyclic AMP-responsive element-binding protein, vitamin D receptor (VDR) and insulin receptor (INSR) gene expression in the diabetic rats when compared with the controls (all P,0·05), while cyclic AMP levels and GLUT2 expression were increased (P,0·05). Treatment of the diabetic rats with vitamin D 3 and insulin reversed the altered parameters to near control values. In conclusion, the data suggest a novel role of vitamin D 3 in restoring impaired liver metabolism in STZ-induced diabetic rats by regulating glucose uptake, storage and metabolism. We demonstrated that the restoring effect of vitamin D 3 is mediated through VDR modulation, thereby improving signal transduction and controlling free radicals in the liver of diabetic rats. These data suggest a potential role for vitamin D 3 in the treatment of diabetes-associated hepatic complications.Key words: Vitamin D: Diabetes: Liver: Oxidative stress: Metabolism: Insulin Diabetes-associated complications are major causes of morbidity and mortality. The liver plays a unique role in glucose homeostasis. Because of its anatomical location, it is ideally suited to control the systemic supply of absorbed nutrients, and it is one of only two organs that both consume and produce substantial amounts of glucose. The central role of the liver in the maintenance of blood glucose levels is assured by complex regulation by metabolic substrates, insulin and other hormones (1) . Diabetes-associated hyperglycaemia and hypoinsulinaemia lead to the impairment of hepatic glucose and lipid metabolism. Virtually, the entire spectrum of liver diseases is seen in patients with diabetes, including liver cirrhosis, a significant cause of death in diabetic patients, even more relevant than CVD (2) . Interest in the development of novel antidiabetic agents has been fuelled by the intense complications due to therapeutic treatment of diabetes and associated liver failure (2,3) . An increased prevalence of diabetes has been observed in vitamin D-deficient individuals (4) , and our previous study has shown that vitamin D 3 treatment restores blood glucose homeostasis in streptozotocin (STZ)-induced diabetic rats (5) . Bind...

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Section: Methodsmentioning

confidence: 99%

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

George¹,

Kumar

Antony

et al. 2012

Br J Nutr

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“…Based on experimental and human studies, the 5-HT2C receptor has been identified as a possible target for anti-obesity drugs [338]. Indeed, the 5-HT2C agonist lorcaserin (APD356) has been identified in rodents and humans to reduce food intake [344,345]. Lorcaserin has relatively few side effects (but 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 27 could be carcinogenic in rats) and has been approved in 2012 by the FDA for long term treatment of obesity [60,346].…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

270

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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“…44 5-HT 2C knockout mice are obese and insulin resistant; the cause of their obesity is hyperphagia, not altered metabolism. 45 One mouse model suggests that 5-HT 2C signaling may also enhance glucose tolerance independently of its effect on body weight. 46 The 5-HT 2B receptor, by contrast, is expressed on cardiac cells and has been implicated as the cause of fenfluramine-associated valvulopathy and pulmonary hypertension.…”

Section: Lorcaserinmentioning

confidence: 99%

“…47 Avoiding 5-HT 2A crossreactivity is also important, as this receptor is implicated in psychosis. 45 Despite the homology of these 3 receptors, lorcaserin activates 5-HT 2C with 18-fold selectivity over 5-HT 2A and 104-fold selectivity over 5-HT 2B in in vitro assays. 45 It has no appreciable activity at other serotonin receptors or receptors for other biogenic amines.…”

Section: Lorcaserinmentioning

confidence: 99%

“…45 Despite the homology of these 3 receptors, lorcaserin activates 5-HT 2C with 18-fold selectivity over 5-HT 2A and 104-fold selectivity over 5-HT 2B in in vitro assays. 45 It has no appreciable activity at other serotonin receptors or receptors for other biogenic amines. 45 This preclinical profile suggests that lorcaserin should not cause valvulopathy or psychiatric side effects because of its high 5-HT 2C selectivity.…”

Section: Lorcaserinmentioning

confidence: 99%

See 1 more Smart Citation

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Cunningham

Wiviott

2014

Clinical Cardiology

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Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. In clinical trials, these drugs cause weight loss and improve glucose tolerance, lipid profile, and, with the exception of bupropion plus naltrexone, blood pressure. However, their effect on cardiovascular outcomes is unknown. In defining appropriate roles for these drugs in preventive cardiology, it is important to remember the checkered history of drugs for obesity. New weight-loss drugs share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of Fen-Phen and sibutramine, respectively, albeit with significant differences. Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety, and potential benefit, of these drugs. This review will discuss the history of pharmacotherapy for obesity, existing efficacy and safety data for the novel weight-loss drugs, and issues in the design of postapproval clinical trials. IntroductionAdvances in prevention-smoking-cessation campaigns, statin therapy, and tight blood pressure (BP) control, among others-have contributed to decreases in the burden of coronary artery disease over the past several decades. However, the increasing prevalence of obesity and obesityassociated diseases like type 2 diabetes mellitus (T2DM) have tempered these gains. 1 Despite recent data suggesting a plateau, rates of obesity remain substantially higher than a few decades ago. 2 Intensive lifestyle interventions have produced clinically relevant weight loss, 3 but modest interventions that are feasible in the primary-care setting are less successful. 4 Many efforts to develop an effective and safe weight-loss pill have failed. In fact, the history of obesity pharmacotherapy has been notable for cardiovascular side effects, not benefits. In 2012, the US Food and Drug Administration (FDA) approved 2 medications for weight loss, the selective 5-HT 2C agonist lorcaserin and the combination pill phentermine plus topiramate; a third, bupropion plus naltrexone, is under consideration for approval at the time of this writing. 5 The mechanisms of

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Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine_2C Agonist: in Vitro and in Vivo Pharmacological Characterization

Cited by 375 publications

References 49 publications

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

Serotonin controlling feeding and satiety

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

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Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization

Cited by 375 publications

References 49 publications

Effect of vitamin D3in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

Effect of vitamin D3in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

Serotonin controlling feeding and satiety

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Contact Info

Product

Resources

About

Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine_2C Agonist: in Vitro and in Vivo Pharmacological Characterization

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats

Effect of vitamin D₃in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats