Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)-one Derivatives

Igawa, Hideyuki; Takahashi, Masashi; Kakegawa, Keiko; Kina, Asato; Ikoma, Minoru; Aida, Jumpei; Yasuma, Tsuneo; Kawata, Y.; Ashina, Shuntaro; Yamamoto, Satoshi; Kundu, Mrinalkanti; Khamrai, Uttam; Hirabayashi, Hideki; Nakayama, Masaharu; Nagisa, Yasutaka; Kasai, Shizuo; Maekawa, Taira

doi:10.1021/acs.jmedchem.5b01704

Cited by 19 publications

(8 citation statements)

References 57 publications

(143 reference statements)

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“…Aside from these indirect actions on feeding, histamine was recently demonstrated to directly control the orexigenic melanin-concentrating hormone (MCH) ( 142 ). Indeed, the MCH receptor antagonists are currently thought of as promising antiobesity agents ( 143 ). As MCH neurons express H-3, but not H-1 or H-2 receptors, it is likely that histamine inhibits MCH secretion via H-3 receptors.…”

Section: Histaminementioning

confidence: 99%

The Obesity–Impulsivity Axis: Potential Metabolic Interventions in Chronic Psychiatric Patients

et al. 2017

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Pathological impulsivity is encountered in a broad range of psychiatric conditions and is thought to be a risk factor for aggression directed against oneself or others. Recently, a strong association was found between impulsivity and obesity which may explain the high prevalence of metabolic disorders in individuals with mental illness even in the absence of exposure to psychotropic drugs. As the overlapping neurobiology of impulsivity and obesity is being unraveled, the question asked louder and louder is whether they should be treated concomitantly. The treatment of obesity and metabolic dysregulations in chronic psychiatric patients is currently underutilized and often initiated late, making correction more difficult to achieve. Addressing obesity and metabolic dysfunction in a preventive manner may not only lower morbidity and mortality but also the excessive impulsivity, decreasing the risk for aggression. In this review, we take a look beyond psychopharmacological interventions and discuss dietary and physical therapy approaches.

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Section: Histaminementioning

confidence: 99%

The Obesity–Impulsivity Axis: Potential Metabolic Interventions in Chronic Psychiatric Patients

et al. 2017

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“…To analyze the effect of TDCA/valine on MCH-regulated appetite and energy homeostasis in vivo, we made use of an MCHR1-I ( Igawa et al, 2016 ). Treatment with MCHR1-I in DIO-obese mice led to decreased food intake and subsequent weight loss ( Figure 5B ).…”

Section: Resultsmentioning

confidence: 99%

Restored TDCA and valine levels imitate the effects of bariatric surgery

Quante

Iske

Heinbokel

et al. 2021

eLife

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Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Methods: Metabolic profiling was performed on diet induced obese (DIO) mice, lean mice and DIO mice that underwent sleeve gastrectomies. In addition, mice were subjected to i.p. injections with TDCA and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with an MCH antagonist and intrathecal administration of melanin-concentrating hormone were performed and weight loss was monitored. Results: Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-Valine levels were restored after sleeve gastrectomies (SGx) in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone. Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

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“…To analyze the effect of TDCA/valine on MCH-regulated appetite and energy homeostasis in-vivo, we made use of a MCH receptor 1 inhibitor (MCHR1-I)( 30 ). Treatment with MCHR1-I in DIO obese mice led to decreased food intake and subsequent weight loss ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery

Tullius

Quante

Iske

et al. 2021

Preprint

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Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities.We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls.Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone.In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

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Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

Cited by 19 publications

References 57 publications

The Obesity–Impulsivity Axis: Potential Metabolic Interventions in Chronic Psychiatric Patients

The Obesity–Impulsivity Axis: Potential Metabolic Interventions in Chronic Psychiatric Patients

Restored TDCA and valine levels imitate the effects of bariatric surgery

Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery

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