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91.
Croston GE Olsson R Currier EA Burstein ES Weiner D Nash N Severance D Allenmark SG Thunberg L Ma JN Mohell N O'Dowd B Brann MR Hacksell U 《Journal of medicinal chemistry》2002,45(23):4950-4953
A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)- 1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a selective nonpeptidic druglike UII receptor agonist, (+)-1 will be useful as a pharmacological research tool and a potential drug lead. 相似文献
92.
Spalding TA Trotter C Skjaerbaek N Messier TL Currier EA Burstein ES Li D Hacksell U Brann MR 《Molecular pharmacology》2002,61(6):1297-1302
Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M(1) muscarinic receptor agonist from a novel structural class. Using a series of chimeric receptors, we demonstrated that this ligand activates the receptor through a region that is not conserved among receptor subtypes, explaining its unprecedented selectivity. This region of the receptor is distinct from the conserved region that is recognized by traditional ligands. The finding that receptors for small-molecule transmitters can have multiple, structurally distinct activation sites has broad implications for the study of receptor structure/function and the potential for the discovery of novel ligands with high selectivity. 相似文献
93.
Hammerness P Ulbricht C Barrette EP Boon H Szapary P Sollars D Smith M Tsourounis C Bent S Basch E 《Journal of herbal pharmacotherapy》2002,2(2):71-93
The use, adverse effects, mechanism of action, pharmacology, interactions and supporting evidence of shark cartilage is presented. Dosage, toxicology and safety parameters are also discussed. 相似文献
94.
Basch E Ulbricht C Hammerness P Tsouronis C Sollars D Rogers A Basch S Bent S Boon H Ernst E 《Journal of herbal pharmacotherapy》2002,2(4):65-91
The proposed uses, dosing parameters, adverse effects, toxicology, interactions and mechanism of action of kava is systematically reviewed in monograph format. 相似文献
95.
Many biological interactions are multivalent, linking two particles via many copies of the same ligand-receptor binding pair. Examples of multivalent binding range from cell-cell adhesion to the assembly of large protein complexes from constituent multimers to the binding of AB5 bacterial toxins at the cell surface. Multivalent interactions can be effectively mimicked, inhibited, or disrupted through the design of suitable multivalent ligands. We review here recent work on multivalent ligand design based on a number of different chemical scaffolds, with a specific emphasis on the use of structure-based ligand design to target multimeric bacterial toxins. 相似文献
96.
A preliminary morphometric magnetic resonance imaging study of regional brain volumes in body dysmorphic disorder 总被引:2,自引:0,他引:2
Rauch SL Phillips KA Segal E Makris N Shin LM Whalen PJ Jenike MA Caviness VS Kennedy DN 《Psychiatry research》2003,122(1):13-19
Morphometric magnetic resonance imaging (MRI) was used to compare regional brain volumes in eight women with body dysmorphic disorder (BDD) and eight healthy comparison subjects. The BDD group exhibited a relative leftward shift in caudate asymmetry and greater total white matter vs. the comparison group. Findings with respect to the caudate nucleus are consistent with both the conceptualization of BDD as an obsessive-compulsive spectrum disorder, and the 'striatal topography model' of obsessive-compulsive disorders. 相似文献
97.
98.
Increased excitability and decreased sensitivity to GABA in an animal model of dysplastic cortex 总被引:7,自引:0,他引:7
PURPOSE: Cortical dysplasia (CD) is associated with epilepsy in both the pediatric and adult populations. The mechanism underlying seizures with cortical malformations is still poorly understood. To study the physiology of dysplastic cortex, we developed an experimental model of CD. METHODS: Pregnant rats were given intraperitoneal injections of carmustine (1-3-bis-chloroethyl-nitrosourea; BCNU) on embryonic day 15 (E15). Cortical histology was examined in the resulting pups at P0, P28, and P60. In addition, evoked and spontaneous field potential recordings were obtained in cortical slices from adult control and BCNU-exposed rats. Finally, we used whole-cell recordings to compare physiologic properties of pyramidal neurons and gamma-aminobutyric acid (GABA) responses in control and BCNU-treated animals. RESULTS: Features characteristic of CD were found in the offspring, including laminar disorganization, cytomegalic neurons, and neuronal heterotopias. Dysplastic cortex also contained abnormal clusters of Cajal-Retzius (CR) cells and disruption of radial glial fibers, as demonstrated with immunohistochemistry. Under conditions of partial GABAA-receptor blockade with 10 microM bicuculline methiodide (BMI), slices of dysplastic cortex demonstrated a significant increase in the number of spontaneous and evoked epileptiform discharges. Individual pyramidal neurons in dysplastic cortex were less sensitive to application of GABA compared with controls. CONCLUSIONS: BCNU exposure in utero produces histologic alterations suggestive of CD in rat offspring. Dysplastic cortex from this model demonstrates features of hyperexcitability and decreased neuronal sensitivity to GABA. Such physiologic alterations may underlie the increased epileptogenicity of dysplastic cortex. 相似文献
99.
Lange LA Lange EM Bielak LF Langefeld CD Kardia SL Royston P Turner ST Sheedy PF Boerwinkle E Peyser PA 《Arteriosclerosis, thrombosis, and vascular biology》2002,22(3):418-423
Coronary artery disease (CAD) is the leading cause of mortality in the developed world. Although several CAD risk factors, including measures of lipid metabolism, obesity, and blood pressure, have a genetic basis, many genes for CAD susceptibility have yet to be identified. Coronary atherosclerosis is the major cause of CAD, but many with coronary atherosclerosis lack symptoms. Thus, a major limitation of using symptomatic CAD endpoints (eg, sudden coronary death, myocardial infarction) as a study outcome is substantial disease misclassification. Coronary artery calcification (CAC) is part of the atherosclerotic process and is an independent predictor of CAD endpoints. In the present study, CAC was noninvasively quantified by electron beam computed tomography. We performed genome-wide multipoint mode-of-inheritance-free linkage analysis on affected sib pairs, defined as being > or = the 70th sex- and age-specific percentile for CAC quantity, in a sample of 29 families enriched for hypertension. Almost 95% of participants were asymptomatic for CAD. Our LOD score (log10 odds in favor of linkage) results provide evidence that chromosomal regions 6p21.3 (maximum LOD score=2.22, P=0.00070) and 10q21.3 (maximum LOD score=3.24, P=0.000057) may harbor genes associated with subclinical coronary atherosclerosis. 相似文献
100.
Klauser A Frauscher F Bodner G Halpern EJ Schocke MF Springer P Gabl M Judmaier W zur Nedden D 《Radiology》2002,222(3):755-761
PURPOSE: To determine the ability of dynamic ultrasonography (US) to depict finger pulley injuries in extreme rock climbers. MATERIALS AND METHODS: Sixty-four extreme rock climbers (climbing levels 8-11 on a scale ranging from 1 to 11; Union Internationale des Associations d'Alpinisme) with finger injuries (75 symptomatic and 181 asymptomatic fingers) were examined by using US, with the transducer operating at 12 MHz. The distance between the flexor tendon and phalanx was evaluated in extension and forced flexion at the level of the A2 and A4 annular pulleys as an indicator of tendon bowstringing. A distance between the flexor tendon and phalanx greater than 1.0 mm was interpreted as positive for a pulley injury. US findings were compared with those of magnetic resonance imaging. Surgical correlation was available in seven cases. Statistical analysis was performed by using analysis of variance, the Student t test, and the Bonferroni method. RESULTS: US depicted 16 (100%) of 16 complete A2 pulley ruptures, nine (100%) of nine complete A4 pulley ruptures, six (86%) of seven surgically proved complete combined A2 and A3 pulley ruptures, and 15 (100%) of 15 incomplete A2 pulley ruptures. Measurement of distance between the flexor tendon and phalanx was significantly different among patient subsets without pulley ruptures and those with incomplete, complete, or complete combined pulley ruptures (P <.001). The sensitivity of US for depiction of finger pulley injuries was 98%, and specificity was 100%. CONCLUSION: Dynamic US allows excellent depiction of finger pulley injuries in extreme rock climbers. 相似文献