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91.
Andrew S. Felts Alice L. Rodriguez Ryan D. Morrison Katrina A. Bollinger Daryl F. Venable Anna L. Blobaum Frank W. Byers Analisa Thompson Gray J. Scott Daniels Colleen M. Niswender Carrie K. Jones P. Jeffrey Conn Craig W. Lindsley Kyle A. Emmitte 《Bioorganic & medicinal chemistry letters》2017,27(21):4858-4866
Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT. 相似文献
92.
Aaron M. Bender Rebecca L. Weiner Vincent B. Luscombe Sonia Ajmera Hyekyung P. Cho Sichen Chang Xiaoyan Zhan Alice L. Rodriguez Colleen M. Niswender Darren W. Engers Thomas M. Bridges P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(15):3576-3581
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp = 2.1, Kp,uu = 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. 相似文献
93.
Marina Yazigi Solis Simon Cooper Ruth M Hobson Guilherme G. Artioli Maria C. Otaduy Hamilton Roschel Jacques Robertson Daniel Martin Vitor S. Painelli Roger C. Harris Bruno Gualano Craig Sale 《PloS one》2015,10(4)
Objectives
Two independent studies were conducted to examine the effects of 28 d of beta-alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2).Methods
In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sex-matched omnivores undertook a brain 1H-MRS exam at baseline and after beta-alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion.Results
In Study 1, there were no within-group effects of beta-alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P<0.05), although there was no effect (P>0.05) of beta-alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise.Conclusion
28 d of beta-alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists. 相似文献94.
Stephen J. Salek Craig V. Sullivan John Godwin 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2001,130(4)
Courtship behaviors are androgen-dependent in many vertebrates and castration often decreases courtship. We examined the effectiveness of castration in reducing courtship behaviors and 11-ketotestosterone (KT) and testosterone (T) in restoring them in male white perch. Castrates were given implants containing KT, T or no hormone. Sham-operated males received implants without hormone. Three weeks later, males were exposed to an ovulated female for 1 h and two courtship behaviors were quantified. Attending behavior involves close and continuous following of a female with occasional contact. Circling involves rapid transits around the female in a circular pattern or back and forth in front of her. In plasma samples taken immediately after observations, KT and T were below detectable levels in castrated males but at high physiological levels in males implanted with KT or T. Castrated males given KT attended females more than castrated males given T implants or implants containing no hormone, but not more than sham-operated males. Circling was eliminated by castration but restored by implantation with T or 11-KT to values exhibited by sham-operated males. This is one of the few demonstrations that KT can regulate courtship behavior in a non-territorial and economically important fish species. 相似文献
95.
Nguyen DN Stump CA Walsh ES Fernandes C Davide JP Ellis-Hutchings M Robinson RG Williams TM Lobell RB Huber HE Buser CA 《Bioorganic & medicinal chemistry letters》2002,12(9):1269-1273
Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements. 相似文献
96.
Arabidopsis consensus intron sequences 总被引:7,自引:0,他引:7
We have analysed 998 Arabidopsis intron sequences in the EMBL database. All Arabidopsis introns to adhere to the :GU...AG: rule with the exception of 1% of introns with :GC at their 5 ends. Virtually all of the introns contained a putative branchpoint sequence (YUNAN) 18 to 60 nt upstream of the 3 splice site. Although a polypyrimidine tract was much less apparent than in vertebrate introns, the most common nucleotide in the region upstream of the 3 splice site was uridine. Consensus sequences for 5 and 3 splice sites and branchpoint sequences for Arabidopsis introns are presented. 相似文献
97.
Catherine L. Craig Gary D. Bernard Jonathan A. Coddington 《Evolution; international journal of organic evolution》1994,48(2):287-296
We measured the reflectance properties of unpigmented silks spun by a systematic array of primitive (Deinopoidea) and derived (Araneoidea) aerial, web-spinning spiders, as well as silks spun by Araneomorphae and Mygalomorphae spiders that do not spin aerial webs. Our data show that all of the primitive aerial web spinners produce catching silks with a spectral peak in the ultraviolet (UV), and cladistic analysis suggests that high UV reflection is the primitive character state for silk spectral properties. In contrast, all of the derived aerial web spinners produce silks that are spectrally flat or characterized by reduced reflectance in the UV. Correlated with the evolution of these catching silks is a 37-fold increase in species number and apparent habitat expansion. This suggests that the unique silk proteins spun by the araneoids have been important to their ecological and evolutionary diversity. 相似文献
98.
Montell C 《Current biology : CB》2003,13(20):R799-R801
TRPM6 and TRPM7 are distinct from all other ion channels in that they are composed of linked channel and protein kinase domains. Recent studies demonstrate that these 'chanzymes' are essential for Mg(2+) homeostasis, which is critical for human health and cell viability. 相似文献
99.
Introduction
Abnormal cancer metabolism creates a glycolytic-dependency which can be exploited by lowering glucose availability to the tumor. The ketogenic diet (KD) is a low carbohydrate, high fat diet which decreases blood glucose and elevates blood ketones and has been shown to slow cancer progression in animals and humans. Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers. Hyperbaric oxygen therapy (HBO2T) saturates tumors with oxygen, reversing the cancer promoting effects of tumor hypoxia. Since these non-toxic therapies exploit overlapping metabolic deficiencies of cancer, we tested their combined effects on cancer progression in a natural model of metastatic disease.Methods
We used the firefly luciferase-tagged VM-M3 mouse model of metastatic cancer to compare tumor progression and survival in mice fed standard or KD ad libitum with or without HBO2T (2.5 ATM absolute, 90 min, 3x/week). Tumor growth was monitored by in vivo bioluminescent imaging.Results
KD alone significantly decreased blood glucose, slowed tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer. While HBO2T alone did not influence cancer progression, combining the KD with HBO2T elicited a significant decrease in blood glucose, tumor growth rate, and 77.9% increase in mean survival time compared to controls.Conclusions
KD and HBO2T produce significant anti-cancer effects when combined in a natural model of systemic metastatic cancer. Our evidence suggests that these therapies should be further investigated as potential non-toxic treatments or adjuvant therapies to standard care for patients with systemic metastatic disease. 相似文献100.
Anja Bengtsson Louise Joergensen Zachary R. Barbati Alister Craig Lars Hviid Anja T. R. Jensen 《PloS one》2013,8(7)
Intercellular adhesion molecule 1 (ICAM-1) is a membrane-bound glycoprotein expressed on endothelial cells and cells of the immune system. Human ICAM-1 mediates adhesion and migration of leucocytes, and is implicated in inflammatory pathologies, autoimmune diseases and in many cancer processes. Additionally, ICAM-1 acts as receptor for pathogens like human rhinovirus and Plasmodium falciparum malaria parasites. A group of related P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains, the DBLβ, mediates ICAM-1 binding of P. falciparum-infected erythrocytes. This ICAM‑1-binding phenotype has been suggested to be involved in the development of cerebral malaria. However, more studies identifying cross-reactive antibody and ICAM-1-binding epitopes and the establishment of a clinical link between DBLβ expression and e.g. cerebral malaria are needed before the DBLβ domains can be put forward as vaccine candidates and go into clinical trials. Such studies require availability of functional recombinant ICAM-1 in large quantities. In this study, we compared recombinant ICAM-1 expressed in HEK293 and COS-7 cells with mouse myeloma NS0 ICAM-1 purchased from a commercial vendor in terms of protein purity, yield, fold, ability to bind DBLβ, and relative cost. We present a HEK293 cell-based, high-yield expression and purification scheme for producing inexpensive, functional ICAM‑1. ICAM-1 expressed in HEK293 is applicable to malaria research and can also be useful in other research fields. 相似文献