作者: Kocum, Courtney G. ; Kocum, Courtney G ; Houska, Tabitha K ; Cam, Yonca ; Schweizer, Tim A. ; Will, Matthew J. ; Konrad, Ella R. ; Will, Matthew J ; Sardina, Carlos A ; Suri, Sanya K. ; Houska, Tabitha K. ; Schweizer, Tim A ; Konrad, Ella R ; Suri, Sanya K ; Sardina, Carlos A.

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. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females.

2014-11-01·European journal of medicinal chemistry1区 · 医学

Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors

1区 · 医学

Article

作者: Xu, Yechun ; Geng, Meiyu ; Yang, Xinying ; Shen, Aijun ; He, Jianhua ; Shen, Jingkang ; Li, Jian ; Yang, Min ; Chen, Wuyan ; Xiong, Bing ; Liu, Hongchun ; Sun, Yiming ; Wang, Yueqin ; Ren, Jing ; Zhang, Liping ; Huang, Min ; Shi, Feng ; Wang, Xin ; Chen, Danqi

HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.

2007-04-01·The Journal of pharmacology and experimental therapeutics3区 · 医学

Efficacy of the MCHR1 Antagonist N-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

3区 · 医学

Article

作者: David, D. J. ; Hen, R. ; Hegde, L. G. ; Zhong, H. ; Marzabadi, M. R. ; Craig, D. A. ; Dong, D. ; Santarelli, L. ; Swanson, C. J. ; Klemenhagen, K. C. ; Holick, K. A. ; Mendez, I. ; Ping, X. I. ; Gerald, C. P. ; Saxe, M. D.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. In rodents, the actions of MCH are mediated via the MCHR1 receptor. The goal of this study was to investigate the effects of acute (1 h) and chronic (28 days) p.o. dosing of a novel MCHR1 antagonist, N-[3-(1-{[4-(3,4-difluorophenoxy)-phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847), in three mouse models predictive of antidepressant/anxiolytic-like activity: novelty suppressed feeding (NSF) in 129S6/SvEvTac mice and light/dark paradigm (L/D) and forced swim test (FST) in BALB/cJ mice. A significant increase in the time spent in the light compartment of the L/D box was observed in response to acute and chronic treatment with SNAP 94847. An anxiolytic/antidepressant-like effect was found in the NSF test after acute and chronic treatment, whereas no effect was observed in the FST. Because neurogenesis in the dentate gyrus has been shown to be a requirement for the effects of antidepressants in the NSF test, we investigated whether neurogenesis was required for the effect of SNAP 94847. We showed that chronic treatment with SNAP 94847 stimulated proliferation of progenitors in the dentate gyrus. The efficacy of SNAP 94847 in the NSF test, however, was unaltered in mice in which neurogenesis was suppressed by X-irradiation. These results indicate that SNAP 94847 has a unique anxiolytic-like profile after both acute and chronic administration and that its mechanism of action is distinct from that of selective serotonin reuptake inhibitors and tricyclic antidepressants.

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