A review of late-stage CNS drug candidates for the treatment of obesity

Heal, David J.; Gosden, Jane; Smith, Sharon L.

doi:10.1038/ijo.2012.26

Cited by 18 publications

(15 citation statements)

References 65 publications

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“…Regarding the recent obesity epidemic, attempts have been made to identify some of these mechanisms as targets for anti-obesity drugs [332][333][334][335][336][337]. The development of anti-obesity drugs is a complex process, last not least due to interactions between satiety systems, the plasticity of satiety systems and the resulting lack of an 'easy' target.…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

“…The development of anti-obesity drugs is a complex process, last not least due to interactions between satiety systems, the plasticity of satiety systems and the resulting lack of an 'easy' target. The clinical use of anti-obesity drugs and the recent trends in the development of anti-obesity drugs has been subject of many reviews [332,[336][337][338] which give also consideration to serotonergic anti-obesity drugs. There are many drugs in different stages of clinical testing, and obviously not all of them recruit the brain 5-HT system for their action.…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

“…Further combinations are being clinically tested [336]. Recent experimental data, however, suggests that this approach does not immediately lead to the expected results.…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

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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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Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

See 1 more Smart Citation

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

270

167

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“…There are 4 new antiobesity agents that have received approval from the US Food and Drug Administration (FDA) for chronic weight management that may exert their weight loss effects through the central nervous system: the combination of phentermine and topiramate extended release, the serotonin 2C receptor agonist lorcaserin, the combination of naltrexone sustained release (SR) and bupropion SR (NB), and a high dose of the long-acting glucagon-like peptide-1 agonist liraglutide (which is already marketed for the treatment of diabetes at a lower dose). 15,16 Importantly, none of the treatments appeared to increase psychiatric adverse events to the extent seen with rimonabant, a cannabinoid receptor type 1 antagonist that has been removed from the market because of an increased incidence of anxiety, depression, and suicidal ideation. All 4 agents also reduced waist circumference and improved metabolic factors, such as serum lipids or glycemic profiles.…”

mentioning

confidence: 99%

The Epidemic of Depression With Obesity

McElroy

2015

J. Clin. Psychiatry

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In this month's issue, Olvera and colleagues 1 provide important findings about the increasingly recognized link among depression, obesity, and metabolic syndrome. 2 Evaluating 1,768 Mexican American adults living on the United States/Mexico border from 2004 to 2010, they found that 30% had current depression, 14% had severe depression, 52% were obese, and 45% had metabolic syndrome. Depression was associated with female gender, low education, low high-density lipoprotein cholesterol, and increased waist circumference, while severe depression was associated with female gender, low education, and extreme obesity. The authors concluded that among Mexican Americans, obesity, female gender, and low education were risk factors for depression.To provide context, these findings can be compared with data from the National Health and Nutrition Examination Survey (NHANES) obtained during a comparable time period, 2005 to 2010. 2 As in Olvera and colleagues 1 study, obesity was defined as a body mass index (BMI) ≥ 30 mg/ kg 2 , BMI was determined from measured (as opposed to self-report) body weight and height, and depression was defined as exceeding a threshold of depressive symptoms over the past 2 weeks. In that data set, 7.2% had current depression and 34.6% were obese; 43% of adults with depression were obese; adults with depression were more likely to be obese than adults without depression; and the proportion of adults with obesity rose as the severity of depressive symptoms increased. Women with depression were more likely to be obese than women without depression in every age group, while this was true of men only in those ≥ 60 years.However, among Mexican American women and men, rates of obesity did not differ by depression status in the NHANES data.2 The relationship between obesity and depression varied by race and ethnicity only among nonHispanic white women. Thus, 46.6% of depressed Mexican American women were obese compared with 43.1% of nondepressed Mexican American women, while among non-Hispanic white women, 45% with depression were obese compared with 32% without depression. It is unknown why Olvera and colleagues' findings are inconsistent with NHANES, but they show that the links among depression, obesity, and metabolic derangement are just as relevant to Mexican American women as they are to other racial/ethnic groups.What do we know about the depression-obesity relationship? As found by Olvera and colleagues, 1 this relationship appears to be stronger in women than in men and with greater severity of depression. 3 Other data show that it is bidirectional 4 and associated with atypical depressive features.5 Thus, obesity increases the risk of onset of depression, and depression predicts development of obesity. A similar bidirectional relationship may exist between depression and metabolic syndrome. It has been hypothesized that obese individuals may develop depression due to the stigma or medical burdens of obesity, as well as the adverse effects of the proinflammatory state of excess adiposity on the...

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“…However, rimonabant has been withdrawn from the market due to concerns about increased risk of suicidal tendencies [1,2]. Anorectic agent sibutramine and phentermine were withdrawn due to cardiovascular issues and the potential for addiction respectively [3][4][5]. Orlistat, a pancreatic lipase inhibitor is the only peripherally acting FDA (Food and Drug Administration) approved the drug for obesity [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Ligand Based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies to Design Novel Pancreatic Lipase Inhibitors

Engels

Divakar

et al. 2017

Int J Pharm Pharm Sci

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Objective: To understand the essential structural features required for pancreatic lipase (PL) inhibitory activity and to design novel chemical entities, ligand-based pharmacophore modeling, virtual screening and docking studies were carried out. Methods:The pharmacophore model was generated based on 133 compounds with PL inhibitory activity using PHASE. An external test set and decoy dataset methods were applied to validate the hypothesis and to retrieve potential PL inhibitors. The generated hypothesis model was further subjected to virtual screening and molecular docking studies. Results:A five point pharmacophoric hypothesis model which consists of three hydrogen bond acceptor sites and two hydrophobic sites was developed. The generated pharmacophore gave significant 3D QSAR (three-dimensional Quantitative Structural Activity Relationship) model with r 2 of 0.9389 and Q 2 value of 0.4016. After database screening, five molecules were found to have better glide scores and binding interactions with the active site amino acid residues. Conclusion:As an outcome of this study, five hit molecules were suggested as potent PL inhibitors as they showed good glide scores as well as binding interactions with required active site amino acids. The five molecules obtained from this study may serve as potential leads for the development of promising anti-obesity agents.

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A review of late-stage CNS drug candidates for the treatment of obesity

Cited by 18 publications

References 65 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

The Epidemic of Depression With Obesity

Ligand Based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies to Design Novel Pancreatic Lipase Inhibitors

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