Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.
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Melanin-concentrating hormone attenuates the hedonic feeding induced by orexin-A in the ventral tegmental area of high-fat diet male mice.
Front Nutr
December 2024
Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.
Objective: The ventral tegmental area (VTA), a pivotal hub in the brain's reward circuitry, receives inputs from the lateral hypothalamic area (LHA). However, it remains unclear whether melanin-concentrating hormone (MCH) and orexin-A (OX-A) neurons in the LHA exert individual or cooperative influence on palatable food consumption in the VTA. This study aims to investigate the modulatory role of MCH and OX-A in hedonic feeding within the VTA of high-fat diet (HFD) mice.
View Article and Find Full Text PDFMelanin-concentrating hormone promotes feeding through the lateral septum.
Prog Neuropsychopharmacol Biol Psychiatry
October 2024
Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address:
Feeding is necessary for survival but can be hindered by anxiety or fear, thus neural systems that can regulate anxiety states are key to elucidating the expression of food-related behaviors. Melanin-concentrating hormone (MCH) is a neuropeptide produced in the lateral hypothalamus and zona incerta that promotes feeding and anxiogenesis. The orexigenic actions of MCH that prolong ongoing homeostatic or hedonic feeding are context-dependent and more prominent in male than female rodents, but it is not clear where MCH acts to initiate feeding.
View Article and Find Full Text PDFIncentive motivation for palatable food blocked by intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonist in female rats.
Pharmacol Biochem Behav
December 2024
Department of Psychological Sciences, University of Missouri, Columbia, MO, USA.
Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food.
View Article and Find Full Text PDFExploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy.
Eur J Med Chem
October 2024
Department of Metabolic Diseases Chemistry, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, NJ, 08543-4000, USA.
With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.
View Article and Find Full Text PDFChronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.
Int J Neuropsychopharmacol
January 2024
Department of Pharmacology, Peking University, School of Basic Medical Science, Beijing, China.
Article Synopsis
- Melanin-concentrating hormone (MCH) in the locus coeruleus (LC) may play a significant role in depression by affecting norepinephrine levels.
- Chronic unpredictable stress (CUS) led to increased MCH levels and decreased MCHR1, which correlated with depression-like behaviors in rats, while blocking MCHR1 showed antidepressant effects.
- The study highlights the potential of the MCH/MCHR1 system in the LC as a target for understanding and potentially treating depression-related mechanisms.
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