Selective 5-HT6 receptor ligands: Progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders

Heal, David J.; Smith, Sharon L.; Fisas, A.; Codony, Xavier; Buschmann, Helmut

doi:10.1016/j.pharmthera.2007.08.006

Cited by 181 publications

(140 citation statements)

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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%

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Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

266

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%

“…5-HT6 receptor antagonists are well tolerated but, despite their satiating effects in rodents, are largely tested towards other indications which include dementia [335].…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

266

167

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“…The 5-HT6 receptor has recently attracted attention as a potential target for the treatment of obesity [35]. 5-HT6 KO animals demonstrated a resistance to weight gain when placed on a high-fat diet.…”

Section: -Ht 6 Antagonists As Potential Obesity Targetsmentioning

confidence: 99%

“…The exact mechanism of 5-HT6-mediated reductions in food intake is unclear. However, 5-HT6 receptor mRNA is found in the ARC and it has been proposed that the blockade of 5-HT6 receptors reduces GABAergic inhibitory control of POMC neurons and the subsequent increase in the release of a-MSH and stimulation of MC-4 receptors leading to a reduction in food intake [35].…”

Section: -Ht 6 Antagonists As Potential Obesity Targetsmentioning

confidence: 99%

New central targets for the treatment of obesity

Sargent

Moore

2009

Brit J Clinical Pharma

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The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation 'New central targets for the treatment of obesity ' (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008). Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non-specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5-HT2c and 5-HT6). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH1 receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co-morbid conditions such as diabetes and cardiovascular disorders. The obesity problemObesity is a major global health problem and rates of obesity [body mass index (BMI) >30 kg m -2 ] have risen steadily year on year. Recent figures show an incidence of obesity of more than 1 in 4 in many parts of the USA [1]. These high rates are similar in other developed countries and the incidence of weight gain is increasing in less developed regions. Obesity is not just a cosmetic or lifestyle illness but leads to many life-threatening health complications. As the BMI increases the incidence of metabolic disorders (Type 2 diabetes), hypertension, cancer and musculoskeletal problems increases [1][2][3]. In 1999, Calle et al. reported mortality rates for all causes doubled when the BMI increased from 25 to >35 [4].The annual direct healthcare costs associated with obesity in the USA are in excess of $93 billion [5]. Particularly worrying is the fact that the incidence of obesity in children and young adults is on the increase, with some reports suggesting that up to 25% of children may be obese. The long-term health implications of these findings are far reaching and suggest that for the first time intergenerational increase in life expectancy will not occur and these children will have a shorter life span than their parents because of health complications associated with weight gain [6] (Figure 1).Obesity occurs when the balance between energy input (food intake) and energy expenditure (exercise, activity) is disrupted, i.e. more food is consumed than utilized, leading to excess fat stores being laid down. Although for some people a calorie-restricted diet and exercise can lead to a reduction in weight gain, for many peop...

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“…We wished to determine whether introduction of piperazinyl methyl group on N 1 -phenylsulfonyl moiety at C-3 0 position would have a desired effect on the binding to 5-HT 6 R and aimed to investigate the structure-activity relationship (SAR). Researchers have developed a pharmacophore model ( Figure 3) for 5-HT 6 receptor antagonists, based on reported chemically diverse 5-HT 6 receptor antagonists [35][36][37][38][39][40][41][42]34 . In this pharmacophore model, four core features were taken into consideration which include the positive ionizable atom (PI, usually a secondary or tertiary amino group), a hydrogen bond acceptor group (HBA, usually a sulfone or sulfonamide group), a hydrophobic site (HYD) and -electron donor aromatic or heterocyclic ring (AR).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders

Nirogi

Bandyala

Gangadasari

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as 5-HT 6 receptor (5-HT 6 R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal models of cognition.

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Selective 5-HT6 receptor ligands: Progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders

Cited by 181 publications

References 106 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

New central targets for the treatment of obesity

Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders

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Selective 5-HT6 receptor ligands: Progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders

Cited by 181 publications

References 106 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

New central targets for the treatment of obesity

Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

Contact Info

Product

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Synthesis and biological evaluation of novel N₁-phenylsulphonyl indole derivatives as potent and selective 5-HT₆R ligands for the treatment of cognitive disorders