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81.
Ding YS Kil KE Lin KS Ma W Yokota Y Carroll IF 《Bioorganic & medicinal chemistry letters》2006,16(4):1049-1053
Using positron emission tomography (PET) with a specific and selective radioligand targeting nicotinic acetylcholine receptor (nAChR) would allow us to better understand various nAChR related CNS disorders. The use of radiolabeled nAChR antagonists would provide a much safer pharmacological profile, avoiding most peripheral side effects that might be generated from radiolabeled nAChR agonists even at the tracer level; thus, PET imaging with nAChR antagonists would facilitate clinical application. A potent and selective nAChR antagonist was labeled and characterized with PET in non-human primates. Its high brain uptake, high signal-to-noise ratio, and high specific binding strongly suggest a great potential to carry out imaging studies in humans. In addition, the use of a C-11 radiotracer would allow us to perform multiple PET studies in the same individual within a short time frame. The presence of an iodine atom in the molecule also allows the possibility to label with radioiodine for SPECT studies. 相似文献
82.
Min Zhong Minna Bui Wang Shen Subramanian Baskaran Darin A. Allen Robert A. Elling W. Michael Flanagan Amy D. Fung Emily J. Hanan Shannon O. Harris Stacey A. Heumann Ute Hoch Sheryl N. Ivy Jeffrey W. Jacobs Stuart Lam Heman Lee Robert S. McDowell Johan D. Oslob Hans E. Purkey Michael J. Romanowski Willard Lew 《Bioorganic & medicinal chemistry letters》2009,19(17):5158-5161
This Letter describes the discovery and key structure–activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314. 相似文献
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84.
Thorsten Thye Edmund N. Browne Margaret A. Chinbuah John Gyapong Ivy Osei Ellis Owusu-Dabo Norbert W. Brattig Stefan Niemann Sabine Rüsch-Gerdes Rolf D. Horstmann Christian G. Meyer 《PloS one》2009,4(5)
Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions −2849 , −1082 , −819 , and −592 and reconstructed the haplotypes. The IL10 low-producer haplotype −2849A/−1082A/−819C/−592C, compared to the high-producer haplotype −2849G/−1082G/−819C/−592C, occurred less frequent among PPD-negative controls than among cases (OR 2.15, CI 1.3–3.6) and PPD-positive controls (OR 2.09, CI 1.2–3.5). Lower IL-10 plasma levels in homozygous −2849A/−1082A/−819C/−592C carriers, compared to homozygous −2849G/−1082G/−819C/−592C carriers, were confirmed by a IL-10 ELISA (p = 0.016). Although we did not observe differences between the TB patients and all controls, our results provide evidence that a group of individuals exposed to M. tuberculosis transmission is genetically distinct from healthy PPD positives and TB cases. In these PPD-negative individuals, higher IL-10 production appears to reflect IL-10-dependent suppression of adaptive immune responses and sustained long-term specific anergy. 相似文献
85.
Monoamine oxidase inhibition byl-deprenyl depends on both sex and route of administration in the rat
The monoamine oxidase B (MAO-B) inhibitorl-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment withl-deprenyl. Significant effects were observed for sex (females showed lower overall MAO-B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness ofl-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug. 相似文献
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87.
Charles J. McElhinny Anita H. Lewin S. Wayne Mascarella Scott Runyon Lawrence Brieaddy F. Ivy Carroll 《Bioorganic & medicinal chemistry letters》2012,22(21):6661-6664
SB-334867 has been an important ligand for the study of the orexin 1 (OX1) receptor due to its high OX1/OX2 selectivity and bioavailability. This ligand however, contains a 2-methylbenzoxazole ring system which is known to undergo hydrolysis, particularly under acidic or basic conditions. The possibility that SB-334867 would be susceptible to significant hydrolysis was evaluated in various formulations and in the solid state. SB-334867 was found to be unstable under conditions commonly employed to prepare stock solutions for in vitro and in vivo studies. In addition, and most alarmingly, the hydrochloride salt of SB-334867 was found to quantitatively decompose to an OX1-inactive product even in the solid state. These findings combine to suggest that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure. 相似文献
88.
Sherratt DJ Søballe B Barre FX Filipe S Lau I Massey T Yates J 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2004,359(1441):61-69
The duplication of DNA and faithful segregation of newly replicated chromosomes at cell division is frequently dependent on recombinational processes. The rebuilding of broken or stalled replication forks is universally dependent on homologous recombination proteins. In bacteria with circular chromosomes, crossing over by homologous recombination can generate dimeric chromosomes, which cannot be segregated to daughter cells unless they are converted to monomers before cell division by the conserved Xer site-specific recombination system. Dimer resolution also requires FtsK, a division septum-located protein, which coordinates chromosome segregation with cell division, and uses the energy of ATP hydrolysis to activate the dimer resolution reaction. FtsK can also translocate DNA, facilitate synapsis of sister chromosomes and minimize entanglement and catenation of newly replicated sister chromosomes. The visualization of the replication/recombination-associated proteins, RecQ and RarA, and specific genes within living Escherichia coli cells, reveals further aspects of the processes that link replication with recombination, chromosome segregation and cell division, and provides new insight into how these may be coordinated. 相似文献
89.
Recent studies have established that the T1R3 receptor plays a central role in the taste-mediated ingestive response to sweeteners by mice. First, transgenic mice lacking the gene for T1R3, Tas1r3, show dramatically reduced lick responsiveness to most sweeteners. Second, strains with the taster allele of Tas1r3 (T strains) are more sensitive to low sweetener concentrations than strains with the nontaster allele (NT strains) and consume greater quantities of low- to midrange concentrations of sweeteners during 24-h tests. We asked how Tas1r3 polymorphisms influence the initial licking responses of four T strains (FVB/NJ, SWR/J, SM/J, and C57BL/6J) and four NT strains (BALB/cJ, 129P3/J, DBA/2J, and C3H/HeJ) to two sweeteners (sucrose and SC-45647, an artificial sweetener). We used the initial licking response as a measure of the taste-mediated ingestive response because its brief duration minimizes the potential contribution of nontaste factors (e.g., negative and positive postingestive feedback). Further, we used two complimentary short-term intake tests (the brief-access taste test and a novel 1-min preference test) to reduce the possibility that our findings were an epiphenomenon of a specific testing procedure. In both tests, the T strains were more responsive than the NT strains to low concentrations of each sweetener. At higher concentrations, however, there was considerable overlap between the T and NT strains. In fact, the initial licking response of several NT strains was more vigorous than (or equivalent to) that of several T strains. There was also considerable variation among strains with the same Tas1r3 allele. We conclude that Tas1r3 polymorphisms contribute to strain differences in initial lick responsiveness to low but not high concentrations of sweeteners. 相似文献
90.