反复摄取烟碱对脑肌醇含量的影响

急性实验中,间隔５ｍｉｎ反复注射烟碱０．５,１．０,１．０,２．０,２．０ｍｇ／ｋｇｉｐ,３０ｍｉｎ后大鼠大脑皮层及海马中肌醇含量升高,但纹状体中肌醇含量无显著变化;相同条件下,氯化锂１０ｍｍｏｌ／ｋｇｉｐ３０ｍｉｎ后大脑皮层和海马中肌醇含量显著降低;慢性实验中,烟碱２．０－１０．０ｍｇ／ｋｇｓｃｂｉｄ１４ｄ后,大鼠大脑皮层中肌醇含量显著增高;烟碱２．６９－１１．５３ｍｇ／ｋｇ／ｄｐｏ６４ｄ后,大鼠大脑皮层中肌醇含量也显著增高。表明烟碱的作用不同于氯化锂,反复给予烟碱可使大鼠大脑皮层中肌醇含量增加。     

胍基丁胺对大鼠血流动力学的影响及其细胞机制

在麻醉大鼠研究静注胍基丁胺（ＡＧＭ）对血流动力学的影响,并初步探讨其机制。结果如下：（１）静注ＡＧＭ（１０ｍｇ／ｋｇ）后,ＨＲ,ＭＡＰ,ＬＶＰ,±ＬＶｄｐ／ｄｔｍａｘ,ＣＩ和ＴＰＲＩ均明显下降;（２）预先静注ＮＯＳ抑制剂ＬＮＮＡ（１５ｍｇ／ｋｇ）或腹腔内注射鸟苷酸环化酶抑制剂亚甲基蓝（５０ｍｇ／ｋｇ）,均不能阻断ＡＧＭ的降压作用;（３）预先静注咪唑啉受体和α２肾上腺素能受体阻断剂ｉｄａｚｏｘａｎ（２ｍｇ／ｋｇ）则可明显阻抑ＡＧＭ的降压效应。以上结果表明,ＡＧＭ对麻醉大鼠的降压机制,在于显著抑制心肌收缩性而使心输出量降低,以及舒张外周血管致使总外周阻力下降;此效应似主要由ＩＲ和／或α２ＡＲ所介导。     

烟碱对氧化震颤素和槟榔碱流涎作用的调节

氧化震颤素和槟榔碱激动唾液腺Ｍ受体剂量依赖性地诱发小鼠流涎,ＥＤ＿（５０）值分别为１１６．２７±２０．１１μｇ／ｋｇｓｃ和９．０２±１．７５ｍｇ／ｋｇｓｃ。烟碱（０．５,１．０ｍｇ／ｋｇｓｃ间隔５ｍｉｎ）预处理后,氧化震颤素和槟榔碱诱发小鼠流涎作用的量效曲线显著左移,ＥＤ＿（５０）值分别降为４３．２５±１１．５２μｇ／ｋｇｓｃ和４．７５±０．７６ｍｇ／ｋｇｓｃ。以美加明阻断Ｎ受体功能后,能对抗烟碱调节Ｍ受体激动剂的流涎作用。以氯化锂抑制肌醇磷酸酶后,能增强烟碱调节Ｍ激动剂的流涎作用。提示烟碱增强唾液腺Ｍ受体对其激动剂的反应性和敏感性,可能与神经元性Ｎ受体干扰唾液腺磷脂酰肌醇代谢有关。     

海人酸诱发癫痫敏感性长期增强的形成与维持

用海人酸（ＫＡ）１０ｍｇ／ｋｇ给Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ大鼠皮下注射，注射后０－３０ｍｉｎ内，动物出现凝视和湿狗样抖动；３０－１２０ｍｉｎ出现时间依赖的癫痫行为；２ｈ后，出现自发反复癫痫发作，４ｈ减弱，８ｈ停止。然后，在上述急性癫痫发作后８，４，２，１周，及１－６ｄ时，分别用阈下剂量ＫＡ（５ｍｇ／ｋｇ）检测癫痫敏感性。结果表明，ＫＡ诱发动物急性癫痫发作后，其癫痫敏感性长期增强，且形成过程是在Ｋ     

MS-551抗缺血性室性心律失常的实验研究

目的：研究新型Ⅲ类抗心律失常药物ＭＳ－５５１,即１,３二甲基－６「２－（Ｎ－２羟乙基－３－４硝苯丙氨基）乙氨基」－２,４（１Ｈ,３Ｈ）－盐酸嘧啶二酮（ＭＳ）,对麻醉犬心肌的电作用和对缺血性室性心律失常的防治效果。方法：测定用药（ＭＳ首剂０．５ｍｇ／ｋｇ于５ｍｉｎ内静推,维持量０．５ｍｇ／ｋｇ静滴３０ｍｉｎ）前后下沉犬心肌房室不应期,并观察ＭＳ「首剂０．３ｍｇ／ｋｇ于５ｍｉｎ内静推,维持量０．５ｍｇ     

投喂保定2号捕捉猕猴的试验

６只体重分别为８￣２０ｋｇ的猕猴、视个体体重情况将１￣２ｍｌ保定２号注入香蕉等食物内投喂,猕猴吃后２０ｍｉｎ左右被捕捉。该药猕猴吃后对呼吸有抑制作用。催醒时一般以回苏２号与保定２号的用量比为１．５：１联合给药较好,即先肌注１／３、接着静注２／３。回苏２号静注２ｍｉｎ左右猕猴呼吸明显增数,接着能很快苏醒。若不苏醒可静脉加注与吃入保定２号一半量的回苏３号。     

双歧杆菌生态制品对海人酸模型抗癫痫作用的初步观察

用海人峻（ＫａｉｎｉｃＡｃｉｄ,ＫＡ）１０ｍｇ／ｋｇ给ＳＤｋ鼠皮下注射,注射后０－１／２ｈ之内,动物出现凝视和湿狗样抖动;１／２－２ｈ,动物出现癫痫发作（严重程度从１级发展至５级）;２ｈ后,动物反复自发出现严重的癫痫发作;４ｈ减弱;８ｈ停止。实验组动物分别于１或３周前开始并连续从饮水中定量投喂双歧杆菌活菌制剂（０．５ｇ／天／只）。结果表明,预先投喂该生态制品持续达３周组大鼠其癫痫发作受到明显抑制与对照组比较Ｐ＜０．０１。     

烟碱对M激动剂诱发脑电癫痫波的影响

在多种动物模型上观察了N激动剂烟碱对中枢M受体介导脑电癫痫波的影响,以研究中枢N受体对M受体功能的调节作用。急性实验以清醒脑电为指标,给两次烟碱(0.5,5.0mg/kg iV,间隔10min)促使大鼠对烟碱产生急性耐受,中枢N受体处于失敏状态下,这时M激动剂槟榔碱和毛果芸香碱诱发大鼠脑电癫痫波的阈值剂量分别由未给两次烟碱时的150mg/kg和380mg/kg降至50mg/     

烟碱对乙酰胆碱诱发豚鼠回肠收缩作用的调节

在离休豚鼠回肠标本上,ＡＣｈ诱发双相收缩反应：早期相收缩反应持续时间短,与神经节Ｎ受体有关;后期相收缩反应持续时间长,与平滑肌Ｍ受体有关。烟碱１０μｍｏｌ／Ｌ预孵育后,标本对烟碱激动神经节Ｎ受体诱发的收缩作用产生急性耐受,而ＡＣｈ激动平滑肌Ｍ受体诱发的收缩作用增强。     

儿童在背负四种不同重量书包下行走时的生理反应

目的和方法：用连续心率监测和气体分析的方法测量了１５名１２岁男孩,在分别负载相当於他们体重１０％,１５％和２０％重的书包,并以不背书包为对照的情况下,以１．１ｍ／ｓ的速度步行２０ｍｉｎ中,停止步行后３ｍｉｎ和５ｍｉｎ的心率、能量消耗和人体工作强度（％最大摄氧量）的变化。受试者的血压亦在步行前,步行后即刻、３ｍｉｎ和５ｍｉｎ予以测量。结果：当受试者负载２０％体重书包行走至５ｍｉｎ时,其能量消耗,摄氧量的变化和相对工作强度较负重０％、１０％和１５％体重行走有显著性差异。     

雄激素和雌激素受体药物筛选方法的研究进展

雄激素和雌激素受体通过与相应激素特异性结合促进细胞分化和组织生长,发挥重要的生理功能,其功能失调可诱发多种疾病。雄激素和雌激素受体的选择性调节剂是治疗相关疾病的重要药物。基于基因组学、分子生物学、细胞生物学和生物信息学等最新研究成果而发展形成的实验技术或方法被用于新型雄激素和雌激素受体调节剂的筛选,显著加快了新药开发的进程。     

Analysis of 3D models of octopus estrogen receptor with estradiol: evidence for steric clashes that prevent estrogen binding

Relatives of the vertebrate estrogen receptor (ER) are found in Aplysia californica, Octopus vulgaris, Thais clavigera, and Marisa cornuarietis. Unlike vertebrate ERs, invertebrate ERs are constitutively active and do not bind estradiol. To investigate the molecular basis of the absence of estrogen binding, we constructed a 3D model of the putative steroid-binding domain on octopus ER. Our 3D model indicates that binding of estradiol to octopus ER is prevented by steric clashes between estradiol and amino acids in the steroid-binding pocket. In this respect, octopus ER resembles vertebrate estrogen-related receptors (ERR), which have a ligand-binding pocket that cannot accommodate estradiol. Like ERR, octopus ER also may have the activation function 2 domain (AF2) in a configuration that can bind to coactivators in the absence of estrogens, which would explain constitutive activity of octopus ER.     

The ecdysteroid receptor

Summary

The steroid molting hormone of insects and other arthropods regulates gene activity in target tissues through its association with a specific, high affinity receptor protein. In this review we summarize recent advances in several areas of ecdysteroid receptor research, including efforts to characterize and purify the receptor protein, cytochemical studies of its tissue distribution and subcellular localization during development, and current molecular genetic studies ecdysteroid action.     

Substituted phenyl as a steroid A-ring mimetic: Providing agonist activity to a class of arylsulfonamide nonsteroidal glucocorticoid ligands

A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.     

降钙素基因相关肽家族受体及其受体活性修饰蛋白

降钙素基因相关肽家族是一类多功能的激素家族 ,参与人体的多种生物学功能 ,与多种疾病有关。降钙素基因相关肽受体包括降钙素受体 (CTR)和降钙素受体样受体 (CRLR) ,CTR可以独自与降钙素结合 ,而CRLR必须与一组称作受体活性修饰蛋白 (RAMPs)的蛋白质共同作用才能发挥生物学功能。综述CTR的研究概况及CRLR与RAMPs相互作用的机制和表达调控 ,以期为人们设计新型药物提供参考。     

Proteinase-activated receptors, nucleotide P2Y receptors, and μ-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking

We recently characterized the proteinase-activated receptor (PAR)-2, a G protein-coupled receptor (GPCR), as the first cargo protein recognized by p24A. Here, we demonstrate that p24A binds to several other GPCRs, including PAR-1, the nucleotide receptors P2Y(1), P2Y(2), P2Y(4), and P2Y(11), as well as the μ-opioid receptor 1B. The acidic amino acid residues Glu and Asp at the second extracellular loop of GPCRs are essential for interaction with p24A. p23, another member of the p24 family, also interacts with GPCRs, similar to p24A. However, p23 shows a delayed dissociation from PAR-2 after activation of PAR-2, compared to the dissociation between PAR-2 and p24A. p24A and p23 arrest both P2Y(4) receptor and μ-opioid receptor 1B at the intracellular compartments, as observed for PAR-2. A comparable result was obtained when we studied primary rat astrocytes in culture. Over-expression of the N-terminal p24A fragment impairs PAR-2 resensitization in astrocytes that extends our findings to a native system. In summary, we demonstrate that p24A and p23 are specific cargo receptors of GPCRs and differentially control GPCR trafficking in the biosynthetic pathway, and thereby, p24A and p23 regulate GPCR signaling in astrocytes.     

Ago-Allosteric Modulation and Other Types of Allostery in Dimeric 7TM Receptors

Conventionally, an allosteric modulator is neutral in respect of efficacy and binds to a receptor site distant from the orthosteric site of the endogenous agonist. However, recently compounds being ago-allosteric modulators have been described i.e., compounds acting both as agonists on their own and as enhancers for the endogenous agonists in both increasing agonist potency and providing additive efficacy—superagonism. The additive efficacy can also be observed with agonists, which are neutral or even negative modulators of the potency of the endogenous ligand. Based on the prevailing dimeric concept for 7TM receptors, it is proposed that the ago-allosteric modulators bind in the orthosteric binding site, but–importantly–in the “other” or allosteric protomer of the dimer. Hereby, they can act both as additive co-agonists, and through intermolecular cooperative effects between the protomers, they may influence the potency of the endogenous agonist. It is of interest that at least some endogenous agonists can only occupy one protomer of a dimeric 7TM receptor complex at a time and thereby they leave the orthosteric binding site in the allosteric protomer free, potentially for binding of exogenous, allosteric modulators. If the allosteric modulator is an agonist, it is an ago-allosteric modulator; if it is neutral, it is a classical enhancer. Molecular mapping in hetero-dimeric class-C receptors, where the endogenous agonist clearly binds only in one protomer, supports the notion that allosteric modulators can act through binding in the “other” protomer. It is suggested that for the in vivo, clinical setting a positive ago-allosteric modulator should be the preferred agonist drug.     

Structural Investigations of Full-Length Insulin Receptor Dynamics and Signalling

Insulin regulates glucose homeostasis via binding and activation of the insulin receptor dimer at two distinct pairs of binding sites 1 and 2. Here, we present cryo-EM studies of full-length human insulin receptor (hIR) in an active state obtained at non-saturating, physiologically relevant insulin conditions. Insulin binds asymmetrically to the receptor under these conditions, occupying up to three of the four possible binding sites. Deletion analysis of the receptor together with site specific peptides and insulin analogs used in binding studies show that both sites 1 and 2 are required for high insulin affinity. We identify a homotypic interaction of the fibronectin type III domain (FnIII-3) of IR resulting in tight interaction of membrane proximal domains of the active, asymmetric receptor dimer. Our results show how insulin binding at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer. We propose an insulin binding and activation mechanism, which is sequential, exhibits negative cooperativity, and is based on asymmetry at physiological insulin concentrations with one to three insulin molecules activating IR.     

新型抗抑郁药物分子靶标研究进展

抑郁症是一种严重的精神障碍疾病,其发病机制复杂。近年来随着对抑郁症发病机制的深入研究,发现了一些基于非单胺递质的 新型抗抑郁药物分子靶标。综述N -甲基-D-天冬氨酸（NMDA）受体、促肾上腺皮质激素释放因子（CRF）受体、阿片受体、γ-氨基丁 酸B(GABAB) 受体、乙酰胆碱受体等抗抑郁药物作用的新靶标及其相应分子机制研究进展,为开发高效、安全的抗抑郁症新药提供参考。