T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist

Takekawa, Shiro; Asami, Asano; Ishihara, Yuji; Terauchi, Jun; Kato, Keita; Shimomura, Yukio; Mori, Masataka; Murakoshi, Hitomi; Kato, Kanefusa; Suzuki, Nobuhiro; Nishimura, Osamu; Fujino, Masahiko

doi:10.1016/s0014-2999(02)01314-6

Cited by 199 publications

(117 citation statements)

References 30 publications

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“…In addition, mice missing the receptor for MCH (MCH1R-KO) are lean, although, in contrast to MCH-KO mice, they are hyperactive and hyperphagic Marsh et al, 2002). Interestingly, systemic administration of an MCH1R antagonist to rodents attenuates feeding, reduces anxiety, and mimics antidepressant effects in the forced swim test (FST) (Borowsky et al, 2002;Takekawa et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The Hypothalamic Neuropeptide Melanin-Concentrating Hormone Acts in the Nucleus Accumbens to Modulate Feeding Behavior and Forced-Swim Performance

Georgescu¹,

Sears²,

Hommel³

et al. 2005

J. Neurosci.

315

279

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Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a prominent role in feeding and energy homeostasis. The rodent MCH receptor (MCH1R) is highly expressed in the nucleus accumbens shell (AcSh), a region that is important in the regulation of appetitive behavior. Here we establish a role for MCH and MCH1R in mediating a hypothalamic-limbic circuit that regulates feeding and related behaviors. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant-like effect in the forced swim test, whereas intra-AcSh injection of MCH had the opposite effect. Expression studies demonstrated that MCH1R is present in both the enkephalin-and dynorphin-positive medium spiny neurons of the AcSh. Biochemical analysis in AcSh explants showed that MCH signaling blocks dopamine-induced phosphorylation of the AMPA glutamate receptor subunit GluR1 at Ser 845 . Finally, food deprivation, but not other stressors, stimulated cAMP response element-binding protein-dependent pathways selectively in MCH neurons of the hypothalamus, suggesting that these neurons are responsive to a specific set of physiologically relevant conditions. This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists.

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Section: Introductionmentioning

confidence: 99%

The Hypothalamic Neuropeptide Melanin-Concentrating Hormone Acts in the Nucleus Accumbens to Modulate Feeding Behavior and Forced-Swim Performance

Georgescu¹,

Sears²,

Hommel³

et al. 2005

J. Neurosci.

315

279

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“…In the recent years, several MCH1-R antagonists such as T-226296 [27], SNAP-7941 [4] or the antagonist characterized by Bednarek et al [1], Shearman et al [23] and Mashiko et al [18] have been developed. These drugs significantly reduce MCH-induced increase in food intake when MCH is injected centrally and the antagonist is given orally (T-226296, [27]), intraperitoneally (SNAP-7941, [4]) or intracerebroventrically [18,23].…”

Section: Introductionmentioning

confidence: 99%

“…These drugs significantly reduce MCH-induced increase in food intake when MCH is injected centrally and the antagonist is given orally (T-226296, [27]), intraperitoneally (SNAP-7941, [4]) or intracerebroventrically [18,23].…”

Section: Introductionmentioning

confidence: 99%

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Morens

Nørregaard²,

Receveur³

et al. 2005

Brain Research

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Receveur, J-M. (2005). Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake. Brain-research, 1062(1-2), 32-38. DOI: 10.1016DOI: 10. /j.brainres.2005 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractMelanin concentrating hormone (MCH) is a regulator of ingestive behavior, but several issues regarding its effects on specific components of ingestive behavior remain to be elucidated. Therefore, we injected, in the 3rd ventricle of male Wistar rats, saline, MCH (5 Ag), MCH (5 Ag) together with a MCH1-R antagonist (A, 10 Ag) and the antagonist alone (A, 10 Ag). Our results show that (1) central administration of MCH stimulates food intake (lab chow and medium high fat diet) and this can be blocked by a MCH1-R antagonist; (2) the MCH-induced increase in food intake is mediated through increased meal number, meal duration and meal size; (3) the MCH1-R antagonist is able to significantly reduce the intake of a highly palatable food (condensed sweet milk) and is more effective in blocking MCH-induced food intake when rats are fed a palatable medium high fat food; and (4) MCH stimulated water intake independently from and disproportionately to food intake. In conclusion, our results point to an involvement of endogenous MCH in the enhanced intake of palatable food. Furthermore, they confirm that MCH stimulates not only food intake but also water intake. D

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“…Some of those have been radio-labeled for in vivo imaging. Clinical trials have been performed for ligands at CRF1 receptors [39,[42][43][44][45][46][47], at orexin receptors [48,49], at the NPY receptors [50,51], the opioid receptors [52], melanocortin -4-receptors (MC4-R) [53][54][55], melanin concentrating hormone receptors (MCH1-R) [56] and growth hormone secretagogue receptor 1 (ghrelin; GHS1-R) [57,58].…”

Section: Hypothalamus As a Potential Target For Drug Development In Tmentioning

confidence: 99%

“…In the Arc leptin depolarizes POMC neurons but hyperpolarizes NPY/GABA/AgRP neurons reducing the transmitter release from these terminals. [56,249] (LHA) releases melanin-concentrating hormone, orexin and NPY [105]. Its neurons communicate with the cerebral cortex where also afferent signals from the vagus nerve and the sympathetic nerve system arrive particularly via nucleus of tractus solitarii (expressing NPY2-R and NPY4-R) what allows the cortical coordination of feeding behavior [104].…”

Section: Endogenous Ligands Of Npy Receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist

Cited by 199 publications

References 30 publications

The Hypothalamic Neuropeptide Melanin-Concentrating Hormone Acts in the Nucleus Accumbens to Modulate Feeding Behavior and Forced-Swim Performance

The Hypothalamic Neuropeptide Melanin-Concentrating Hormone Acts in the Nucleus Accumbens to Modulate Feeding Behavior and Forced-Swim Performance

Effects of MCH and a MCH1-receptor antagonist on (palatable) food and water intake

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

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