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71.
Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1 总被引:1,自引:0,他引:1
Tavares FX Al-Barazanji KA Bigham EC Bishop MJ Britt CS Carlton DL Feldman PL Goetz AS Grizzle MK Guo YC Handlon AL Hertzog DL Ignar DM Lang DG Ott RJ Peat AJ Zhou HQ 《Journal of medicinal chemistry》2006,49(24):7095-7107
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity. 相似文献
72.
Tavares FX Al-Barazanji KA Bishop MJ Britt CS Carlton DL Cooper JP Feldman PL Garrido DM Goetz AS Grizzle MK Hertzog DL Ignar DM Lang DG McIntyre MS Ott RJ Peat AJ Zhou HQ 《Journal of medicinal chemistry》2006,49(24):7108-7118
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents. 相似文献
73.
Immunoferon (AM3) enhances the activities of early-type interferon inducers and natural killer cells
P Moya E Baixeras I Barasoain J M Rojo E Ronda M L Alonso A Portolés 《Immunopharmacology and immunotoxicology》1987,9(2-3):243-256
The "in vivo" effect of Immunoferon (AM3) on the production of interferon (IFN) and natural killer (NK) activity in young and old mice was studied. Although AM3 is not an IFN inducer by itself, enhancements in the serum IFN levels were produced when drug was associated to Newcastle disease virus or bacterial lipopolysaccharides as IFN inducers. This effect appeared to be dependent on the time lapsed between the inducer agent and drug. In addition, a significant stimulating effect on NK cell activity was also produced by AM3 treatments. This effect could be a consequence of a marked IFN induction and/or a modifying effect in prostaglandin synthesis. 相似文献
74.
In reply 总被引:4,自引:0,他引:4
Community coalitions have become popular vehicles for promoting health. Which factors make coalitions effective, however, is unclear. The study's aim was to identify coalition-building factors related to indicators of coalition effectiveness through a review of the empirical literature. Published articles from 1980 to 2004 that empirically examined the relationships among coalition-building factors and indicators of coalition effectiveness were reviewed. Two indicators of coalition effectiveness were examined: coalition functioning and community-wide changes. A two-phase strategy was employed to identify articles by reviewing citations from previous literature reviews and then searching electronic reference databases. A total of 1168 non-mutually exclusive citations were identified, their abstracts reviewed, and 145 unique full articles were retrieved. The review yielded 26 studies that met the selection criteria. Collectively, these studies assessed 26 indicators of coalition effectiveness, with 19 indicators (73%) measuring coalition functioning, and only two indicators (7%) measuring changes in rates of community-wide health behaviors. The 26 studies identified 55 coalition-building factors that were associated with indicators of coalition effectiveness. Six coalition-building factors were found to be associated with indicators of effectiveness in five or more studies: formalization of rules/procedures, leadership style, member participation, membership diversity, agency collaboration, and group cohesion. However, caution is warranted when drawing conclusions about these associations due to the wide variations in indicators of coalition effectiveness and coalition-building factors examined across relatively few studies, discrepancies in how these variables were measured, and the studies' reliance on cross-sectional designs. 相似文献
75.
Klimberg VS Kepple J Shafirstein G Adkins L Henry-Tillman R Youssef E Brito J Talley L Korourian S 《Annals of surgical oncology》2006,13(11):1422-1433
Introduction Excision followed by RFA (eRFA) may allow improved cosmesis while ensuring negative margins in patients with breast cancer. This technique utilizes heat to create an additional tumor-free zone around the lumpectomy cavity. We hypothesized that eRFA will decrease the need for re-excision of inadequate margins.Methods Between July 2002 and January 2005, we conducted a multiphase trial of RFA of prophylactic mastectomy specimens and of women desiring lumpectomy. In both models, a lumpectomy was performed, the RFA probe was deployed 1 cm circumferentially into the walls of the lumpectomy cavity and maintained at 100°C for 15 min. Whole mount slides were used to measure the zone of ablation for ex vivo specimens. Hematoxylin and eosin staining of in vivo lumpectomy margins <3 mm was considered inadequate.Results Nineteen prophylactic mastectomy ablations revealed a consistent perimeter of ablation. Forty-one patients (mean age 63 ± 14 years) had an average tumor size of 1.6 ± 1.5 cm underwent in vivo eRFA, and 25% had inadequate margins: one focally positive, one <2 mm, eight <1 mm and one grossly positive. Only the grossly positive margin was re-excised. Overall complication rate of in vivo ablations was 7.5%. Twenty-four of 41 patients did not have post-eRFA XRT. No in-site local recurrences have occurred during a median follow-up of 24 months (12–45 months). Two patients have occurred elsewhere.Conclusions The ex vivo ablation model reliably created a 5–10 mm perimeter of ablation. In vivo, this zone reduced the need for re-excision for inadequate margins by 91% (10/11). Short-term follow-up suggests that eRFA could reduce re-excision surgery and local recurrence. 相似文献
76.
77.
Previous research has demonstrated that shame-proneness (the tendency to feel bad about the self) relates to a variety of life problems, whereas guilt-proneness (the tendency to feel bad about a specific behavior) is more likely to be adaptive. The current analyses sought to clarify the relations of shame-proneness and guilt-proneness to substance use problems in three samples with differing levels of alcohol and drug problem severity: college undergraduates (Study 1 N=235, Study 2 N=249) and jail inmates (Study 3 N=332). Across samples, shame-proneness was generally positively correlated with substance use problems, whereas guilt-proneness was inversely related (or unrelated) to substance use problems. Results suggest that shame and guilt should be considered separately in the prevention and treatment of substance misuse. 相似文献
78.
Freeman TL Haver A Duryee MJ Tuma DJ Klassen LW Hamel FG White RL Rennard SI Thiele GM 《Chemical research in toxicology》2005,18(5):817-824
Cigarette smoke is a risk factor for the development of several diseases, but the exact mechanism responsible has not been well-characterized. Because modification, or adducting, of biomolecules is thought to mediate the toxic effects observed from exposure to a wide variety of harmful chemicals, this study investigated the ability of cigarette smoke to produce specific adducts on a peptide to gain insight into the likely effect on cellular proteins. We describe the modification of the epsilon-amino group of lysine contained in a test peptide with stable fluorescent adducts derived from monofunctional aldehydes occurring in cigarette smoke and malonaldehyde, a product of lipid peroxidation. Utilizing high-performance liquid chromatography, fluorescent measurements, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, the 1,4-dihydropyridine-3,5-dicarbaldehyde and 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde derivatives of lysine were identified as products of exposure to cigarette smoke extract and malonaldehyde. These data suggest that cigarette smoke may promote the modification of proteins, like those associated with oxidized low-density lipoprotein, and may contribute to smoking-related disease. 相似文献
79.
80.
Ronda C Borba SC Ferreira SC Glotz D Ianhez LE Rodrigues H Viggiani CS Nahas W David-Neto E Castro MC David Daisa SR Kalil J Panajotopoulos N 《Transplantation proceedings》2011,43(4):1345-1348
Preformed donor-specific human leukocyte antigen (HLA) antibodies have been associated with allograft dysfunction and failure. However, recipients of HLA-identical kidneys can develop acute humoral rejection, implicating putative pathogenic antibodies that are directed against non-HLA antigens. We investigated the presence of endothelial cell-reactive antibodies in 11 patients who experienced early loss of their transplanted kidneys owing to humoral rejection and 1 loss from renal venal thrombosis. We examined the potential efficacy of intravenous immunoglobulin to block the binding of these antibodies, as previously suggested for anti-HLA antibodies. 相似文献