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81.
82.
The effects of long-term treatment (three times a day for 3 weeks) with pharmacologically active doses of the novel anxiolytics and anticovulsants abecarnil (0.5 mg/kg, IP) and imidazenil (0.5 mg/kg, IP) on basal hippocampal acetylcholine release in freely moving rats were compared with those of diazepam (3 mg/kg, IP). Challenge doses of diazepam, abecarnil, and imidazenil decreased the extracellular acetylcholine concentration in the hippocampus by the same extent in animals chronically treated with the respective drug or vehicle. Moreover, the abrupt discontinuation of long-term treatment with diazepam, abecarnil, or imidazenil failed to affect hippocampal acetylcholine release during the first 5 days of withdrawal. In contrast, the acute administration of the benzodiazepine receptor antagonist flumazenil (1 mg/kg, IP) 2 days after diazepam withdrawal elicited a marked increase (65%) in acetylcholine release in the hippocampus. Flumazenil failed to induce the same effect 5 days after diazepam withdrawal or 2 or 5 days after discontinuation of long-term treatment with abecarnil or imidazenil. These results indicate that (i) the inhibitory effects of full (diazepam), partial (imidazenil), and selective (abecarnil) benzodiazepine receptor agonists on acetylcoholine output in rat hippocampus are not affected by repeated drug administration; (ii) discontinuation of long-term treatment with each type of agonist does not affect hippocampal cholinergic mechanisms; and (iii) flumazenil increases acetylcholine release only in the hippocampus of rats chronically treated with diazepam. Together, these data further differentiate the pharmacology of benzodiazepine receptor full agonists from that of partial and selective agonists. 相似文献
83.
JL Mokrosz B Duszyńska S Charakchieva-Minol AJ Bojarski MJ Mokrosz RL Wydra L Janda L Strekowski 《European journal of medicinal chemistry》1996,31(12):973-980
New N-methylpiperazino-substituted quinazolines 8 and 9, phthalazine 13, and quinoline 19 have been synthesized. The receptor binding profiles (α1, 5-HT1A, 5-HT2A) of these compounds and their analogs (7–22) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α1 and 5-HT2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α1 ligand (Ki = 4.9 nM) with a much lower affinity for 5-HT1A (Ki = 3420 nM) and 5-HT2A (Ki = 211 nM) receptors. 相似文献
84.
RALPH-HEIKO MATTERN YUSUkE AMINO ETTORE BENEDETTI MURRAY GOODMAN 《Chemical biology & drug design》1997,50(4):286-299
Four potent sweet-tasting molecules, N-(3, 3-dimethylbutyl)-l -aspartyl-l -phenylalanine methylester 1 (7000 times more potent than sucrose), N-(3, 3-dimethylbutyl)-l -aspartyl-d -valine (S)-α-ethylbenzylamide 2 (3000 time more potent than sucrose), l -aspartyl-d -valine (R)-α-methoxymethylbenzylamide 3 (1350 times more potent than sucrose and l -aspartyl-(1R, 2S, 4S)-1-methyl-2-hydroxy-4-phenylhexylamide 4 (2500 times more potent than sucrose) were studied by H NMR and computer simulations. These flexible molecules adopt multiple conformations in solution. The “L-shaped” structure, which we believe to be responsible for sweet taste is accessible to all four compounds in solution. Extended conformations with the AH and B-containing moieties in the +y-axis and the hydrophobic group X pointing in the y-axis have also been observed for all four sweeteners. For compounds 1 and 3 , the solid-state conformations were determined by X-ray diffraction studies. These results demonstrate that compounds 1 and 3 adopt an “L-shaped” structure even in the crystalline state. The extraordinary potency of the N-alkylated compound 1 compared with the unsubstituted Asp-Phe-OMe may be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the “L-shaped” structure. 相似文献
85.
人FLT3配体的克隆、表达与纯化 总被引:2,自引:1,他引:1
目的 克隆人FLT3配体(Flt3Ligand,FL)基因,并在大肠杆菌中对FL进行表达、纯化。方法 分离人外周血单个核细胞,提取总RNA,采用R T-巢式PCR扩增人FLT3配体胞外段基因,以双脱氧终止法进行DNA序列分析;将测序正确的目的基因克隆入大肠杆菌融合表达载体pRSET-B;处重组质粒pRSET-B-FL转化大肠杆菌BL21(DE3),用IPTG进行诱导后,收集细菌、菌体裂解后,利用常压离子交换色谱的方法对表达蛋白进行纯化,并进行SDS-PAGE及Westernblot检测。结果 从人外周血单个核细胞中克隆得到长462bp的FL基因,测序正确;经EcoR Ⅰ和Hind Ⅲ酶切鉴定证实,FL成功地克隆到表达载体pRSET-B;构建的表达载体pRSET-B-FL在大肠杆菌中表达出Mr24000的融合蛋白,经常压离子交换色谱化后的融合蛋白的纯度达到90%,该融合蛋白具有FL抗原特性。结论 成功地克隆并表达了FL基因,并对融合蛋白进行了初步纯化 ,为大规模获得FL创造了条件。 相似文献
86.
Izyaslav P. Lapin 《Neuroscience and biobehavioral reviews》1983,7(2):107-118
Kynurenine, an endogenous cerebral and peripheral neuroactive metabolite of l-tryptophan, exerts stimulant and convulsant effects in mice, rats and frogs. In mice it (intracerebroventricularly, ICV) antagonized the anticaffeine effect of diazepam and in smaller doses potentiated its sedative action. In rats l-kynurenine (ICV) potentiated the convulsant action of caffeine. The effect of pentylenetetrazol was not altered in either species. The convulsant effect of l-kynurenine is the most resistant among various convulsants towards the protective action of diazepam. The structure of l-kynurenine is similar to benzophenones, metabolites of diazepam, and has four structural fragments common with diazepam. Putative endogenous and non-endogenous ligands of the benzodiazepine receptors have from one to three of these common fragments. Among the antagonists of diazepam exhibiting stimulant and convulsant action ethyl-β-carbonline-3-carboxylate has the same four fragments, Ro 5–3663 and Ro 15–1788 have three and caffeine two. The most striking dissimilarity is a diazo-moiety (NCCN or NCCC N) absent in the structure of l-kynurenine. This moiety seems to be the most important for the binding to the benzodiazepine receptors. A role of each fragment and their combinations as well as the stereoconfiguration for the pharmacological activity is considered. It is suggested that l-kynurenine is a putative endogenous modulator or, less probably, ligand of the benzodiazepine receptor of either type (most probably that which mediates anxiolytic action of benzodiazepines) or a part of this receptor. The benzodiazepine receptor might be a phylogenetically transformed kynurenine receptor. Highly selective antagonism of purines to l-kynurenine suggests that it can modulate the function of the benzodiazepine receptors via purinergic mechanisms. Stimulant and convulsant action of l-kynurenine can be related to a moiety of succinic acid (OCCCCO) which is typical of quinolinic acid, the strongest endogenous convulsant among kynurenines, and aspartic acid, an excitatory amino acid. l-Kynurenine is suggested to be an anxiogenic and convulsigenic endogenous factor. 相似文献
87.
N. J. Prakash Paul J. Schechter Eugene Giroux Albert Sjoerdsma 《Clinical and experimental pharmacology & physiology》1977,4(1):17-26
1. Gavage of rats with β-aryl derivatives of α-mercaptoacrylic acid resulted in pronounced and sustained elevation of serum zinc concentration. Greater than ten-fold increases above normal zinc levels were attained 2–8 h after doses of 50 mg/kg of the phenyl and furan derivatives. 2. These compounds were rapidly absorbed from the rat gastrointestinal tract and could be detected in serum for several days after a single dose. The return of serum zinc concentration to the normal level paralleled clearance of the mercaptoacrylic acid from plasma. 3. Close to 100% of the zinc and of the α-mercapto-β-(2-furan)acrylic acid (MFA) in serum 4 h after administration of the compound were bound to serum macromolecules. 4. MFA decreased excretion of endogenous zinc; it altered neither the gastrointestinal absorption of zinc nor serum concentrations of copper, albumin and total protein. 5. These compounds appear to mobilize zinc from tissue stores and retard zinc clearance from plasma. 相似文献
88.
Eugene Giroux N. J. Prakash Paul J. Schechter 《Clinical and experimental pharmacology & physiology》1977,4(1):27-35
1. Four, six and eight hours after gavage of rats with α-mercapto-β-(2-furan) acrylic acid (MFA) (25 mg/kg) serum zinc concentration was increased ten-fold over control levels and a mean molar ratio of 1 albumin:0.4 zinc:0.8 MFA was found for seventeen sera. 2. At pH 7.5 a maximum of 1 mole of MFA could be bound per mole of metal-free bovine serum albumin. 3. In the presence of zinc ion, albumin-zinc-MFA complexes formed, since for each mole of albumin-zinc complex an additional mole of MFA could be bound to albumin. Complexes up to a molar stoichiometry of 1 albumin:2 zinc:3 MFA were prepared. 4. MFA stabilized the albumin-zinc complex against dissociation. 5. Formation of similar complexes in vivo may account for the markedly delayed clearance of plasma zinc seen in rats administered β-aryl derivatives of α-mercaptoacrylic acid. 相似文献
89.
A S Lippa C A Klepner L Yunger M C Sano W V Smith B Beer 《Pharmacology, biochemistry, and behavior》1978,9(6):853-856
The in vitro and in vivo ability of benzodiazepines to inhibit specific 3H-diazepam binding correlated with their ability to increase punished responding in a conflict situation. Conflict and foot shock, the punishing stimulus used in most conflict procedures, also altered 3H-diazepam binding. These data implicate 3H-diazepam binding sites in mediating at least some of the anxiolytic properties of benzodiazepines and suggest the existence of some endogenous substance which might be involved in the etiology of anxiety. 相似文献
90.
S J Cooper 《Brain research bulletin》1985,15(4):397-410
A classical approach to the control of food consumption has been to assume separate mechanisms for the arousal to eat, on the one hand, and the satiation of feeding responses, on the other. The present paper is concerned with a single, and a comparatively simple, neuronal mechanism which is endowed with properties to allow the complete determination of the level of feeding, from hyperphagia to anorexia. The model for the control of feeding, which is presented here, draws attention to the benzodiazepine receptor found distributed through the brain, and present in certain hypothalamic nuclei. Recent evidence which characterizes the receptor is reviewed, and the various categories of benzodiazepine receptor ligands are described. Pharmacological data, collected in a palatable food consumption model using non-food-deprived rats, demonstrate that benzodiazepine receptor agonists produce hyperphagia, benzodiazepine receptor inverse agonists produce anorexia, and benzodiazepine receptor antagonists block both effects. Hence, bidirectional control of food intake can be achieved through differential ligand action at a common set of receptors. Speculatively, these data can be extended, if it is assumed that two endogenous ligands exist in the brain which act like benzodiazepine agonist and inverse agonist, respectively. Evidence for the presence in hypothalamic nuclei of endogenous ligands of the latter kind is discussed. Benzodiazepine withdrawal-induced anorexia is also described, and is taken as evidence for the part played by feeding mechanisms in the development of benzodiazepine physical dependence. 相似文献