Structure-activity studies on 4-substituted-2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists

Structure-activity studies around the 4-position of 2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists suggest that there is a large lipophilic cavity in the rat CRF receptor, which can accommodate a wide variety of substituents at this position in contrast to the steric constraints observed for other positions on the 2-anilinopyrimidine core. The chemical syntheses and biological activities of 2-anilinopyrimidine CRF antagonists with carbon-linked substituents at the 4-position are reported. Significant improvements in rat pharmacokinetic parameters were achieved relative to those for the lead structure. While the lead compound 1 (rCRF Ki = 44 nM) afforded no detectable rat plasma levels after intraperitoneal (i.p.) or oral (p.o.) dosing, compounds 3-3 (rCRF Ki = 16 nM) and 3-4 (rCRF Ki 59 nM) gave high rat plasma levels at 30 mg/kg (i.p., p.o.) (Cmax = 1389 nM and 8581 nM (i.p.) respectively; Cmax = 113 nM and 988 nM (p.o.), respectively). Furthermore 3-3 and 3-4 had superior bioavailabilities at these doses (59 and 46% (i.p.), respectively; 2 and 10%, (p.o.), respectively).     

Production of S-(+)-2-phenylpropionic acid from (R,S)-2-phenylpropionitrile by the combination of nitrile hydratase and stereoselective amidase in Rhodococcus equi TG328

A new soil isolate, tentatively identified as Rhodococcus equi TG328, was found to be effective in the production of S-(+)-2-phenylpropionic acid from (R,S)-2-phenylpropionitrile. The conversion is catalysed by two enzymes. First, a nitrile hydratase converts the (R,S)-nitrile to (R,S)-2-phenylpropionamide. Second, a stereoselective amidase converts the S-(+)-amide to S-(+)-2-phenylpropionic acid. Conditions for optimal enzyme production and accumulation of S-(+)-2-phenylpropionic acid by resting cells were studied. The reaction of resting cells for 30 h at 10° C with (R,S)-2-phenylpropionitrile resulted in the production of 100 g of S-(+)-2-phenylpropionic acid per litre of reaction mixture. The enantiometric excess of the purified S-(+)-2-phenylpropionic acid was 99.4%. The amount of S-(+)-2-phenylpropionic acid accumulated was enhanced by lower reaction temperatures. In addition, unreacted R-(–)-2-phenylpropionamide with 99.0% enantiometric excess was isolated. Correspondence to: T. Nagasawa     

昆虫抗药性和昆虫毒理动力学(英文)

不断地使用一种杀虫药剂防治昆虫,会导致昆虫产生抗药性。对昆虫抗药性资料进行广泛综述时,发现了仅单独的解毒作用不能被解释为家蝇对有机氯杀虫药剂产生高抗性原因。作为一个基因。家蝇可以对有机氯产生比对有机磷杀虫剂更高的抗药性,尽管有机磷杀虫剂一般在虫体内是不太稳定的。考虑到昆虫毒理的动力学,杀虫药剂的穿透作用更显示出其实际的重要性。根据穿透和解毒的速率,慢的穿透作用是解毒作用的一个限制因子。防治敏感和抗性昆虫的观察结果,可以划出物理和生物因子之间关系的几种相关曲线图解。这些相关性不仅能说明家蝇对有机磷和有机氯杀虫剂的抗性程度,而且也助于选择出新的杀虫毒剂。     

A radioimmunoassay for measuring alpha-amidating enzyme activity.

A sensitive alpha-amidating enzyme (alpha AE) assay using C-terminal glycine-extended substance P (SP-Gly) as a substrate was developed. The product, substance P (SP), was measured by a radioimmunoassay with specific polyclonal antibodies which recognize SP with an affinity 10,000-fold higher than that of SP-Gly. The sensitivity of the radioimmunoassay was 5 fmol. Enzyme activity could be readily detected with 25 ng alpha AE partially purified from the conditioned medium of rat medullary thyroid carcinoma CA-77 cells. The Km and Vmax values were 2.0 +/- 0.2 microM and 1.7 +/- 0.1 nmol/mg/min (mean +/- SE, n = 3), respectively. The assay enabled the kinetic characterization of alpha AE from a single rat pituitary homogenate. Optimal Cu2+ required was 30 microM and greater than 3 mM of ascorbate was needed for maximal enzyme activity. The sensitivity of this assay will aid efforts to examine the regulation of in vivo alpha AE activity.     

Measurement on Camber Deformation of Wings of Free-flying Dragonflies and Beating-flying Dragonflies

1　IntroductionNumerouskinematicparameters,includingwing beatfrequency ,wingorientation ,andbothspan andchord wisedeformation ,arerelevanttotheaerodynam icanalysisofinsectflight[1,2 ] .Althoughnearlyalltherecentstudiesofinsectflightaerodynamics[3,4 ] haveidentifiedthatthemechanismsrequireflowseparationattheleadingedge ,andcamberisnotexpectedtohaveanysignificantinfluenceonthemagnitudeoftheforcecoefficient,someinsects ,suchasdragonfliesandbut terflies,frequently glideusinglowanglesofattack ,lead…     

Microsatellites reveal a high population structure in Triatoma infestans from Chuquisaca, Bolivia

Background

For Chagas disease, the most serious infectious disease in the Americas, effective disease control depends on elimination of vectors through spraying with insecticides. Molecular genetic research can help vector control programs by identifying and characterizing vector populations and then developing effective intervention strategies.

Methods and Findings

The population genetic structure of Triatoma infestans (Hemiptera: Reduviidae), the main vector of Chagas disease in Bolivia, was investigated using a hierarchical sampling strategy. A total of 230 adults and nymphs from 23 localities throughout the department of Chuquisaca in Southern Bolivia were analyzed at ten microsatellite loci. Population structure, estimated using analysis of molecular variance (AMOVA) to estimate F_ST (infinite alleles model) and R_ST (stepwise mutation model), was significant between western and eastern regions within Chuquisaca and between insects collected in domestic and peri-domestic habitats. Genetic differentiation at three different hierarchical geographic levels was significant, even in the case of adjacent households within a single locality (R _ST = 0.14, F _ST = 0.07). On the largest geographic scale, among five communities up to 100 km apart, R _ST = 0.12 and F _ST = 0.06. Cluster analysis combined with assignment tests identified five clusters within the five communities.

Conclusions

Some houses are colonized by insects from several genetic clusters after spraying, whereas other households are colonized predominately by insects from a single cluster. Significant population structure, measured by both R _ST and F _ST, supports the hypothesis of poor dispersal ability and/or reduced migration of T. infestans. The high degree of genetic structure at small geographic scales, inferences from cluster analysis and assignment tests, and demographic data suggest reinfesting vectors are coming from nearby and from recrudescence (hatching of eggs that were laid before insecticide spraying). Suggestions for using these results in vector control strategies are made.