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991.
Cha JH Zou MF Adkins EM Rasmussen SG Loland CJ Schoenenberger B Gether U Newman AH 《Journal of medicinal chemistry》2005,48(24):7513-7516
Novel fluorescent ligands were synthesized to identify a high-affinity probe that would enable visualization of the dopamine transporter (DAT) in living cells. Fluorescent tags were extended from the N- or 2-position of 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)tropane, using an ethylamino linker. The resulting 2-substituted (5) and N-substituted (9) rhodamine-labeled ligands provided the highest DAT binding affinities expressed in COS-7 cells (Ki= 27 and 18 nM, respectively) in the series. Visualization of the DAT with 5 and 9 was demonstrated by confocal fluorescence laser scanning microscopy in stably transfected HEK293 cells. 相似文献
992.
Lund BW Piu F Gauthier NK Eeg A Currier E Sherbukhin V Brann MR Hacksell U Olsson R 《Journal of medicinal chemistry》2005,48(24):7517-7519
4'-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARbeta2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained beta2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARbeta2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development. 相似文献
993.
Guerrini R Caló G Lambert DG Carrá G Arduin M Barnes TA McDonald J Rizzi D Trapella C Marzola E Rowbotham DJ Regoli D Salvadori S 《Journal of medicinal chemistry》2005,48(5):1421-1427
Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1-13)-NH(2) and [Nphe(1)]N/OFQ(1-13)-NH(2) as a N/OFQ peptide receptor (NOP) partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe(4) or the insertion of a further pair of basic amino acids Arg(14)-Lys(15) generate potent agonists. On the basis of these findings, we combined in the N/OFQ-NH(2) template the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) that increase the agonist potency with those conferring partial agonist (Phe(1)Psi(CH(2)NH)Gly(2)) or pure antagonist (Nphe(1)) properties. Twelve peptides were synthesized and pharmacologically evaluated in Chinese hamster ovary cells expressing the human recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum assays. All peptides behaved as NOP ligands; the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) increased ligand affinity/potency. Peptides with the normal Phe(1)-Gly(2) peptide bond behaved as full agonists, and those with the Phe(1)Psi(CH(2)NH)Gly(2) modification behaved as partial agonists, while those with the Nphe(1) modification behaved as partial agonists or pure antagonists depending on the presence or absence of the (pF)Phe(4) modification, respectively. The full agonist [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), the partial agonist [Phe(1)Psi(CH(2)NH)Gly(2),(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), and the pure antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) represent the most potent peptide ligands for NOP. 相似文献
994.
Jakab B Helyes Z Varga A Bölcskei K Szabó A Sándor K Elekes K Börzsei R Keszthelyi D Pintér E Petho G Németh J Szolcsányi J 《European journal of pharmacology》2005,517(1-2):35-44
The TRPV1 capsaicin receptor is an integrator molecule on primary afferent neurones participating in inflammatory and nociceptive processes. The present paper characterizes the effects of JYL1421 (SC0030), a TRPV1 receptor antagonist, on capsaicin-evoked responses both in vitro and in vivo in the rat. JYL1421 concentration-dependently (0.1-2 microM) inhibited capsaicin-evoked substance P, calcitonin gene-related peptide and somatostatin release from isolated tracheae, while only 2 microM resulted in a significant inhibition of electrically induced neuropeptide release. Capsazepine (0.1-2 microM), as a reference compound, similarly diminished both capsaicin-evoked and electrically evoked peptide release. JYL1421 concentration-dependently decreased capsaicin-induced Ca(2+) accumulation in cultured trigeminal ganglion cells, while capsazepine was much less effective. In vivo 2 mg/kg i.p. JYL1421, but not capsazepine, inhibited capsaicin-induced hypothermia, eye wiping movements and reflex hypotension (a component of the pulmonary chemoreflex or Bezold-Jarisch reflex). Based on these data JYL1421 is a more selective and in most models also a more potent TRPV1 receptor antagonist than capsazepine, therefore it may promote the assessment of the (patho)physiological roles of the TRPV1 receptor. 相似文献
995.
Antal M Regöly-Mérei A Nagy K Greiner E Biró L Domonkos A Balajti A Szórád I Szabó C Mozsáry E 《Annals of nutrition & metabolism》2004,48(5):307-313
BACKGROUNDS/AIMS: To assess the age- and gender-specific anthropometric parameters and blood pressure in Hungarian adolescents. METHODS: A cross-sectional study was performed between 1997 and 2000. Altogether 6,345 secondary school students (aged 15-18 years) were involved in the study. The representative sampling sites were selected randomly. In the capital city 3-stage and in the counties 4-stage stratified groups were assigned for the studies. Statistical analysis was performed using SPSS for Windows 9.0. RESULTS: The age- and gender-specific percentile distributions are given with regard to body weight, body height, body mass index (BMI), waist circumference, waist-to-hip ratio and arterial blood pressure values. Elevated blood pressure values were found at the first recording in 14.1% of the boys and in 2.5% of the girls. Since it is well known that the arterial blood pressure (ABP) may exhibit considerable intra- individual fluctuation with time, we therefore categorized normotensive and hypertensive students on the basis of the mean ABP values calculated from data obtained during the course of the three separate consecutive measurement periods at least 2 weeks apart. After that, the incidence of high blood pressure was 7.5% in boys and 1.1% in girls. CONCLUSION: The age- and gender-specific cutoff values thus formed may serve as reference values to assess the risk of developing nutrition-related noninfectious diseases in the future on the basis of the present percentile distribution of BMI. The present study also provides data on the prevalence of hypertension in the 15- to 18-year-old age group. 相似文献
996.
997.
998.
Maura Faraci Ilaria Caviglia Erika Biral Giuseppe Morreale Stefano Giardino Lucia Garbarino Elio Castagnola Giorgio Dini Edoardo Lanino 《Pediatric transplantation》2012,16(8):887-893
a‐GvHD may complicate allogeneic HSCT. In this retrospective single‐center study, we evaluated incidence and risk factors of a‐GvHD in 197 consecutive allogeneic pediatric HSCTs applying Glucksberg and NIH a‐GvHD classifications. Among 179 eligible transplants, the cumulative incidence of grade 0–I a‐GvHD was 48% and grade II–IV was 52%. None of the considered variables significantly influenced the incidence of grade II–IV a‐GvHD. Malignancy and myeloablation were associated with an increased risk of classic a‐GvHD (p < 0.01). Seventy‐two percentage of children are alive, with a significant difference in OS and TRM between grade 0 and I vs. grade II and IV a‐GvHD; this observation was reproduced in the non‐malignant setting, while only a disparity in TRM was evidenced in children with malignancy. In our experience, the incidence of a‐GvHD was similar, regardless of donor type. Myeloablation and malignant disease represented the only risk factors for classic a‐GvHD. Our results highlight the need for a better prevention of this complication in the non‐malignant setting. 相似文献
999.
1000.
Nelson-Wong E Appell R McKay M Nawaz H Roth J Sigler R Third J Walker M 《European journal of applied physiology》2012,112(4):1379-1389
Falls are a leading contributor to disability in older adults. Increased muscle co-contraction in the lower extremities during
static and dynamic balance challenges has been associated with aging, and also with a history of falling. Co-contraction during
static balance challenges has not been previously linked with performance on clinical tests designed to ascertain fall risk.
The purpose of this study was to investigate the relationship between co-contraction about the ankle during static balance
challenges with fall risk on a commonly used dynamic balance assessment, the Four Square Step Test (FSST). Twenty-three volunteers
(mean age 73 years) performed a series of five static balance challenges (Romberg eyes open/closed, Sharpened Romberg eyes
open/closed, and Single Leg Standing) with continuous electromyography (EMG) of bilateral tibialis anterior and gastrocnemius
muscles. Participants then completed the FSST and were categorized as ‘at-risk’ or ‘not-at-risk’ to fall based on a cutoff
time of 12 s. Co-contraction was quantified with co-contraction index (CCI). CCI during narrow base conditions was positively
correlated with time to complete FSST. High CCIs during all static balance challenges with the exception of Romberg stance
with eyes closed were predictive of being at-risk to fall based on FSST time, odds ratio 19.3. The authors conclude that co-contraction
about the ankle during static balance challenges can be predictive of performance on a dynamic balance test. 相似文献