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21.
22.
Wilna J. Moree Florence Jovic Timothy Coon Jinghua Yu Bin-Feng Li Fabio C. Tucci Dragan Marinkovic Raymond S. Gross Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Zhihong O’Brien Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(7):2316-2320
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound. 相似文献
23.
Wilna J. Moree Bin-Feng Li Said Zamani-Kord Jinghua Yu Timothy Coon Charles Huang Dragan Marinkovic Fabio C. Tucci Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Kayvon Jalali Chun Yang Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(19):5874-5878
Analogs of the known H1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. 相似文献
24.
We are testing the idea that placement of fixed charges near one face of the DNA double helix can induce DNA bending by a purely electrostatic mechanism. If stretching forces between DNA phosphates are significant, fixed charges should induce DNA bending by asymmetrically modulating these forces. We have previously tested this hypothesis by adding charged residues to small bZIP DNA binding peptides and monitoring DNA bending using electrophoretic phasing assays. Our results were consistent with an electrostatic model of DNA bending in predicted directions. We now confirm these observations with fluorescence resonance energy transfer (FRET). Using a "U"-shaped DNA probe, we report that DNA bending by charged bZIP peptides is readily detected by FRET. We further show that charged bZIP peptides cause DNA bending rather than DNA twisting. 相似文献
25.
The aim of the study was to determine the impact of demographic and anthropometric parameters on the gastric myoelectrical activity characteristics in a healthy Croatian population. The influence of age, sex, body mass index (BMI) and menstrual cycle phase on the gastric myoelectrical activity characteristics was assessed. The study included 120 healthy subjects of both sexes (60 male and 60 female), divided into four age groups (18-35, 36-50, 51-65 and > 65 years) and three BMI groups (BMI < 25, 25-30 and > 30). Female subjects of reproductive age were divided into three groups according to menstrual cycle phase (day 1-3, day 4-8 and day 9-20 of menstruation). All study subjects underwent percutaneous electrogastrography (EGG) for 60 min before and 60 min after a test meal. The following parameters of the gastric myoelectrical activity were observed: dominant frequency (DF); dominant frequency within normal range (DFNR, %); coefficient of variation for dominant frequency (CVDF); dominant strength (DS. mV); postprandial increase intensity in dominant strength (PPIIDS, %); bradygastria (BG, c/min, %); tachygastria (TG, c/min, %); and arrhythmia (AR). Age was found to influence preprandial but not postprandial DFNR, CVDF and AR. Sex influenced preprandial DF, CVDF, DS and BG, and postprandial DF, CVDF, PPIIDS and TG. BMI exerted an impact on preprandial TG and AR, and postprandial DF, CVDF and AR. The phase of menstrual cycle influenced DF in preprandial period and none of EGG parameters in postprandial period. 相似文献
26.
The aim of this study is to evaluate connection of plasma level of beta2-microglobulin, C-reactive protein and uric acid as well as sonographic parameters like thickness of synovial membrane, thickness of femoral condylar cartilage and presence of joint effusion and Baker's cysts with bilateral knee pain in dialyzed patients, comparing them with parameters in asymptomatic dialyzed patients. Plasma levels of beta2-microglobulin and C-reactive protein were significantly higher in symptomatic patients while uric acid level showed no difference among the groups. In symptomatic patients synovial membrane was thicker and in those patients there were more knee effusions and Baker's cysts. Thickness of femoral condylar cartilage showed no difference between groups. That suggests that inflammatory mechanisms developing from beta2-microglobulin accumulation could be important factor in bilateral knee pain in dialyzed patients even in shorter duration dialysis. 相似文献
27.
Jiang W Tran JA Tucci FC Fleck BA Hoare SR Markison S Wen J Chen CW Marinkovic D Arellano M Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2007,17(23):6546-6552
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats. 相似文献
28.
29.
Markovic G Jukic I Milanovic D Metikos D 《Journal of strength and conditioning research / National Strength & Conditioning Association》2007,21(2):543-549
The purpose of this study was to evaluate the effects of sprint training on muscle function and dynamic athletic performance and to compare them with the training effects induced by standard plyometric training. Male physical education students were assigned randomly to 1 of 3 groups: sprint group (SG; n = 30), plyometric group (PG; n = 30), or control group (CG; n = 33). Maximal isometric squat strength, squat- and countermovement jump (SJ and CMJ) height and power, drop jump performance from 30-cm height, and 3 athletic performance tests (standing long jump, 20-m sprint, and 20-yard shuttle run) were measured prior to and after 10 weeks of training. Both experimental groups trained 3 days a week; SG performed maximal sprints over distances of 10-50 m, whereas PG performed bounce-type hurdle jumps and drop jumps. Participants in the CG group maintained their daily physical activities for the duration of the study. Both SG and PG significantly improved drop jump performance (15.6 and 14.2%), SJ and CMJ height ( approximately 10 and 6%), and standing long jump distance (3.2 and 2.8%), whereas the respective effect sizes (ES) were moderate to high and ranged between 0.4 and 1.1. In addition, SG also improved isometric squat strength (10%; ES = 0.4) and SJ and CMJ power (4%; ES = 0.4, and 7%; ES = 0.4), as well as sprint (3.1%; ES = 0.9) and agility (4.3%; ES = 1.1) performance. We conclude that short-term sprint training produces similar or even greater training effects in muscle function and athletic performance than does conventional plyometric training. This study provides support for the use of sprint training as an applicable training method of improving explosive performance of athletes in general. 相似文献
30.
Manuela Murariu Ecaterina Stela Dragan Adriana Adochitei Gheorghita Zbancioc Gabi Drochioiu 《Journal of peptide science》2011,17(7):512-519
The role of silver ions in various pathologies, as well as their effect on peptide conformation and properties are less understood. Consequently, we synthesized several peptides with various residues in their sequence to investigate silver‐induced conformational changes at various pH values by Circular Dichroism spectroscopy. Uniquely, the glycine‐based, histidine‐containing peptide showed a severe change from a random coil and β‐turn conformation to large α‐helices during silver binding. When comparing the effect of silver ions on the conformation of bradykinin a similar tendency was found. Besides, silver ions reduced the amyloid‐β peptide tendency to aggregation. Our results suggest a specific and protective role for silver ions in brain pathologies, which is related to their high affinity toward physiologically and pharmacologically active peptides. Fourier transform infrared spectroscopy studies as well as the mass spectrometric ones support our conclusions. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. 相似文献