Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites*

The clinical use of currently available drugs acting at the5-HT₄ receptor has been hampered by their lack of selectivityover 5-HT₃ binding sites. For this reason, there is considerableinterest in the medicinal chemistry of these serotonin receptor subtypes, andsignificant effort has been made towards the discovery of potent and selectiveligands. Computer-aided conformational analysis was used to characterizeserotoninergic 5-HT₃ and 5-HT₄ receptorrecognition. On the basis of the generally accepted model of the5-HT₃ antagonist pharmacophore, we have performed a receptormapping of this receptor binding site, following the active analog approach(AAA) defined by Marshall. The receptor excluded volume was calculated as theunion of the van der Waals density maps of nine active ligands(pK_i 8.9), superimposed in pharmacophoric conformations.Six inactive analogs (pK_i < 7.0) were subsequently used todefine the essential volume, which in its turn can be used to define theregions of steric intolerance of the 5-HT₃ receptor. Five activeligands (pK_i 9.3) at 5-HT₄ receptors wereused to construct an antagonist pharmacophore for this receptor, and todetermine its excluded volume by superimposition of pharmacophoricconformations. The volume defined by the superimposition of five inactive5-HT₄ receptor analogs that possess the pharmacophoric elements(pK_i 6.6) did not exceed the excluded volume calculated forthis receptor. In this case, the inactivity may be due to the lack of positiveinteraction of the amino moiety with a hypothetical hydrophobic pocket, whichwould interact with the voluminous substituents of the basic nitrogen ofactive ligands. The difference between the excluded volumes of both receptorshas confirmed that the main difference is indeed in the basic moiety. Thus,the 5-HT₃ receptor can only accommodate small substituents inthe position of the nitrogen atom, whereas the 5-HT₄ receptorrequires more voluminous groups. Also, the basic nitrogen is located at ca.8.0 Å from the aromatic moiety in the 5-HT₄ antagonistpharmacophore, whereas this distance is ca. 7.5 Å in the5-HT₃ antagonist model. The comparative mapping of bothserotoninergic receptors has allowed us to confirm the three-componentpharmacophore accepted for the 5-HT₃ receptor, as well as topropose a steric model for the 5-HT₄ receptor binding site. Thisstudy offers structural insights to aid the design of new selective ligands,and the resulting models have received some support from the synthesis of twonew active and selective ligands: 24 (K_i(5-HT₃)= 3.7 nM; K_i(5-HT₄) > 1000 nM) and 25(K_i(5-HT₄) = 13.7 nM;K_i(5-HT₃) > 10 000 nM).     

BCEIA 2001学术报告会论文作者调查研究

对BCEIA2001学术报告会论文作者问卷调查资料进行统计分析，我国从事分析测试科研活动的人员以青年人为主，且具有高学历、高职称的特点；分析测试领域的科研活动主要集中在北京、湖北、辽宁、广东、上海等省市；分析测试领域的研究主要涉及分析测试物质的成份、结构以及提高分析测试质量；当前分析测试领域的研究热点在化学／化工、环保、生物技术、卫星／临床、制药等领域；分析测试领域研究工作的资金主要来源于各种基金的支持。     

A new adsorbent for trace level organic contaminants

Summary A preliminary study has been carried out to evaluate a new adsorbent, Thermosorb, for trace level organic contaminants. For this purpose, a comparison was made with a well-characterized adsorbent, Tenax GC, using a prepared aqueous solution of trace organic components. In addition, a comparison was made of chromatograms of air contaminants obtained using both of these adsorbents, under equivalent conditions. The results clearly indicated the potential of this thermally stable, inorganic adsorbent for many trace organic substances of environmental interest.     

Analytical techniques for cyanide in blood and published blood cyanide concentrations from healthy subjects and fire victims

Hydrogen cyanide can be produced by the pyrolysis of man-made polymers. Cyanide has been measured in the blood of healthy adults as well as the blood of fire survivors and fatalities. In healthy subjects the blood cyanide concentration of smokers is higher than that of non-smokers. Fire survivors and fatalities have been found to have higher cyanide levels than of control groups and the levels from fire fatalities are often higher than survivors. Blood concentrations quoted as normal, toxic or fatal are highly variable in the literature. Many studies have been performed to measure the blood cyanide levels in control subjects as well as those who have been exposed to fire but the values found differ. The values for control subjects can vary from none detected to 19 μmol dm⁻³ while those for fire survivors range from not detected to 150 μmol dm⁻³ and fatalities range from not detected to 284 μmol dm⁻³. Analytical techniques and published data are critically reviewed.Many of the existing antidotes for cyanide poisoning are highly toxic themselves and should ideally be administered at doses proportional to the amount of cyanide a patient has received to avoid compounding damage done by cyanide intoxication. For this reason, a rapid, accurate bedside assay of blood cyanide concentration that differentiates between bound and free cyanide would represent a leap forward in the clinical management of cyanide poisoning.     

Double pulse laser-induced breakdown spectroscopy of explosives: Initial study towards improved discrimination

Detecting trace explosive residues at standoff distances in real-time is a difficult problem. One method ideally suited for real-time standoff detection is laser-induced breakdown spectroscopy (LIBS). However, atmospheric oxygen and nitrogen contributes to the LIBS signal from the oxygen- and nitrogen-containing explosive compounds, complicating the discrimination of explosives from other organic materials. While bathing the sample in an inert gas will remove atmospheric oxygen and nitrogen interference, it cannot practically be applied for standoff LIBS. Alternatively, we have investigated the potential of double pulse LIBS to improve the discrimination of explosives by diminishing the contribution of atmospheric oxygen and nitrogen to the LIBS signal. These initial studies compare the close-contact (< 1 m) LIBS spectra of explosives using single pulse LIBS in argon with double pulse LIBS in atmosphere. We have demonstrated improved discrimination of an explosive and an organic interferent using double pulse LIBS to reduce the air entrained in the analytical plasma.     

二氧化碳/环氧丙烷/γ-丁内酯三元共聚物微球降解性的研究

动物体内的体液和肠胃等器官的环境各不相同，这就要求各种不同用途的载药体的降解性能必须满足特定环境的要求。同时，可降解材料在不同的降解介质中通常有着不同的降解表现，这也决定着可降解材料的运用环境。因此，有必要对降解性材料在不同降解介质中的降解性进行专门的研究，由CO2和环氧化物合成的脂肪族聚碳酸酯具有良好的生物降解性能。     

毛细管胶束电动色谱对复方药物有效成分的定量研究

本文报道采用毛细管胶束电动色谱法对复方药物去痛片和感冒灵中有效成分进行了分离和定量研究。以0.05毫米内径、45厘米长的弹性石英毛细管为分离柱,用十二烷基硫酸钠胶束溶液,在选定的实验条件下,各组分在十几分钟内就能很好的分离。采用两点内标法定量,所得结果与HPLC法测定结果相一致。该法具有装置简单,无需价格昂贵的分离柱,样品预处理简单等优点,可在药物分析中推广。     

臭椿籽挥发油的化学成分分析

采用水蒸气蒸馏法对甘肃天水产的臭椿籽挥发油进行提取，挥发油得率约为2．1％(w)；用气相色谱-质谱联用技术对挥发性成分进行了分析，鉴定了43个化合物，占挥发油相对含量的96．3％；主要成分为脂肪酸及酯、脂肪烃及甾族化合物，其中含量较高的有亚油酸、油酸、蓖麻酸和蓖麻酸甲酯。