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1.
Analogues and derivatives of six of the amino acids which most effectively inhibit protein degradation in isolated rat hepatocytes (leucine, asparagine, glutamine, histidine, phenylalanine and tryptophan) were investigated to see if they could antagonize or mimic the effect of the parent compound. No antagonists were found. Amino alcohols and amino acid amides tended to inhibit protein degradation strongly, apparently by a direct lysosomotropic effect as indicated by their ability to cause lysosomal vacuolation. Amino acid alkyl esters and dipeptides inhibited degradation to approximately the same extent as did their parent amino acids, possibly by being converted to free amino acids intracellularly. Of several leucine analogues tested, four (L-norleucine, L-norvaline, D-norleucine and L-allo-isoleucine) were found to be as effective as leucine in inhibiting protein degradation. None of the analogues had any effect on protein synthesis. Since leucine appears to play a unique role as a regulator of bulk autophagy in hepatocytes, the availability of active leucine agonists may help tj elucidate the biochemical mechanism for control of this important process.  相似文献   

2.
R A Baffi  J M Becker  P N Lipke  F Naider 《Biochemistry》1985,24(13):3332-3337
Five des-Trp1,Cha3,X6 analogues of alpha-factor, where X = Ala, Val, Ile, Nle, or D-Leu and X = Leu in the natural alpha-factor sequence, were prepared by solution-phase techniques utilizing isobutyl chloroformate or 1-hydroxybenzotriazole accelerated active esters as the coupling agents. Purification to 98% or greater homogeneity was accomplished by high-performance liquid chromatography on a reversed-phase muBondapak C18 column with methanol/water/trifluoroacetic acid as the mobile phase. Three of the synthesized analogues (X6 = Val, Ile, Nle) induced morphogenesis and increased agglutinability in a cells. These substitutions demonstrate that a gamma-branched side chain at position 6 is not essential for biological activity. All of the active analogues induced morphogenesis at lower concentrations than they induced enhanced agglutinability. These results and other structure-activity relationships [Baffi, R. A., Shenbagamurthi, P., Terrance, K., Becker, J. M., Naider, F., & Lipke, P. (1984) J. Bacteriol. 158, 1152-1156] indicate that the agglutination and morphological responses to alpha-factor can be varied independently. Replacement of Leu6 with Ala or D-Leu resulted in inactive analogues that were not antagonistic for alpha-factor activity. Cell-mediated hydrolysis experiments indicated that the biological activities of the alpha-factor analogues are independent of their rates of degradation. All position 6 analogues were hydrolyzed more slowly than the parent compound, suggesting that the enzyme which degrades alpha-factor is highly specific for the native structure.  相似文献   

3.
Selective inhibition of the localized excess production of NO by neuronal nitric oxide synthase (nNOS) has been targeted as a potential means of treating various neurological disorders. Based on observations from the X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-amino)ethylamino]pentyl}-N'-nitroguanidine (L-Arg(NO2)-L-Dbu-NH2 (1) and 4-N-(Nomega-nitro-L-argininyl)-trans-4-amino-L-proline amide (2), a series of descarboxamide analogues was designed and synthesized (3-7). The most potent compound was aminopyrrolidine analogue 3, which exhibited better potency and selectivity for nNOS than parent compound 2. In addition, 3 provided higher lipophilicity and a lower molecular weight than 2, therefore having better physicochemical properties. Nalpha-Methylated analogues (8-11) also were prepared for increased lipophilicity of the inhibitors, but they had 4- to 5-fold weaker binding affinity compared to their parent compounds.  相似文献   

4.
The ability of thyrotrophin-releasing hormone (TRH), its metabolites and several analogues to induce wet-dog shaking (WDS) was tested by their injection into the periaqueductal grey region of male rats. TRH and its metabolite deamido-TRH (TRH-OH) both stimulated WDS, though TRH-OH gave a longer duration of response; other TRH metabolites were inactive. Of the TRH analogues studied, RX77368 (pGlu-His-3,3'-dimethyl-ProNH2) was the most potent in this behavioural test system. Both CG3509 and CG3703 were also very active in inducing WDS, as were their deamidated metabolites. The relative stability of the TRH analogues to enzymic degradation in the brain may be related to their enhanced behavioural activity over TRH. The production from these analogues of biologically-active metabolites may also explain the increased activity in stimulating WDS of the parent peptides.  相似文献   

5.
Fluphenazine (FPh) exhibited antimutagenic activity in lymphocyte cultures, markedly decreasing genotoxic effects of standard mutagenic agents present in cell cultures. However, the strong pharmacological activity of this neuroleptic drug, together with its serious side effects on the central nervous system, limits its use as an antimutagenic compound. In this paper we describe a route of chemical synthesis of FPh analogues that are more hydrophilic than the model compound, thus probably penetrate more weakly through the blood-brain barrier. These new analogues were tested for their antimutagenic and pro-apoptotic activities in human lymphocyte cultures, genotoxically damaged in vitro with benzo[a]pyrene [40 microM, 30 min] and subsequently cultured for 48 h in the presence of the tested compounds. The fluphenazine analogues enhanced apoptosis in genotoxically damaged lymphocytes more strongly than the model compound did. The increase of apoptotic cell frequency was the highest with compound 4a [2-(trifluoromethyl)-10-[3-(diethanolamino)-2-hydroxypropyl] phenothiazine]--a 35% higher effect than that of fluphenazine. The cytotoxicity of derivative 4a was the lowest among the tested compounds; it was 60% lower than that of fluphenazine. The antimutagenic effect of 4a was about 10% stronger than that of fluphenazine. Compound 4a also had the highest hydrophilicity of the new FPh analogues. Compound 4a was chosen for further study as a potentially usable antimutagen that would only weakly penetrate the central nervous system.  相似文献   

6.
Five analogs of leucine enkephalin containing the CH2S group as an amide bond replacement were evaluated with respect to resistance toward degradation by human serum in an HPLC-based assay using both ultraviolet and electrochemical detection. Analogs with the modification at the 1-2, 2-3, 3-4, or 4-5 peptide linkages demonstrated half-lives of 118, 85, 134, and 318 min vs. 12 min for the parent peptide. A pseudopeptide analog with additional D-Ala2 protection had a half-life of greater than 1000 min, while the potent [D-Ala2]-leucine enkephalin analog showed approximately a 10-fold increase in stability. The significant increase in stability for a compound with protection only at the C-terminus suggests that serum enzymes may have greater specificity toward backbone changes than previously realized.  相似文献   

7.
To increase the therapeutic utility of C-18 side-chain bearing pseudomycin analogue 2, we prepared additional analogues and prodrugs of 2 containing further modifications at various positions within its core structure. Each of the newly synthesized derivatives (10-15) exhibited reduced tail vein toxicity relative to the parent compound. Some of the new pseudomycin derivatives (e.g., 14) also showed improved in vivo antifungal activity relative to its corresponding parent compound.  相似文献   

8.
9.
Chlorogenic acid derivatives are potent inhibitors of hepatic glucose production by inhibition of the glucose-6-phosphate translocase component of the hepatic glucose-6-phosphatase system. The pharmacological proof of concept was clearly demonstrated during i.v. infusion of potent derivatives (S 4048, S 3483) in rats. However, the blood glucose lowering effect of S 4048 after bolus i.v. injection lasted only 60-90 min. Plasma clearance of S 4048 was very high, and the parent compound was rapidly and efficiently excreted into the bile of Wistar and GY/TR(-) rats, indicating that mrp-2 was not involved in this hepatobiliary elimination process. About 72% of the total administered radioactivity appeared in the bile within 20 min after i.v. bolus injection of the radiolabeled analogue [(3)H]S 1743 in a Wistar rat. However, in GY/TR(-) rats the dicarboxylic analogue of S 4048, S 3025, was cleared from the plasma less rapidly than its parent compound and its biliary elimination was comparatively low. In contrast, S 3025 exhibited comparable pharmacokinetics and biliary elimination profile as S 4048 in Wistar rats, suggesting that biliary elimination of S 3025 is facilitated by mrp-2, functionally absent in GY/TR(-) rats. Targeting to mrp-2 resulted in a significantly prolonged reduction of blood glucose levels in GY/TR(-) rats after i.v. bolus administration of S 3025.  相似文献   

10.
Fluoroalkyl and fluoroaryl analogues of valdecoxib were found to possess potent inhibitory activities against cyclooxygenase-2 comparable to that of the parent valdecoxib. Among them, the fluoromethyl analogue was chosen for 18F-labeling. Thus, 4-(5-[18F]fluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide (approximately 2000 Ci/mmol at end of synthesis) was synthesized by [18F]fluoride-ion displacement of the corresponding tosylate in approximately 40% decay-corrected radiochemical yield within approximately 120 min from end of bombardment.  相似文献   

11.
Substrate analogues based on the parent compounds paraoxon and phenyl acetate were tested on human serum paraoxonase (PON1) to explore the active site of the enzyme. Replacement of the nitro group of paraoxon with an amine or hydrogen, as well as electronic changes to the parent compound, converted these analogues into inhibitors. Introduction of either electron-withdrawing or donating groups onto phenyl acetate resulted in reduction in their rate of hydrolysis by PON1.  相似文献   

12.
Chlorisondamine (CHL), a neuronal nicotinic ganglionic blocker, when injected in the cerebral ventricle of rats chronically blocks the increase in locomotion and rearing by subcutaneous nicotine injection. The blocking of the ion channel(s) prevents nicotine from exerting its rewarding effects on the CNS. When administered intraperitoneally, a dose 400-500 times the intracerebroventricular one is needed to cross the blood-brain barrier and to generate the same level of nicotine antagonism, resulting in severe side-effects, thus making it unlikely to be used as a therapeutical compound. Three CHL analogues, 2-(indolin-1-yl)-N,N,N-trimethylethanaminium iodide, 2-(1,3-dioxoisoindolin-2-yl)- N,N,N-trimethylethanaminium iodide, and 2-(1H-indole-3-carboxamido)- N,N,N-trimethylethanaminium iodide, were synthesized in the hope of circumventing the parent compound's shortcomings. They all share a modified indole ring, lack the four chlorines CHL carries, and have one tertiary amine and one quaternary amine. The CHL analogues form noncovalent complexes with an epitope of the alpha-2 nicotinic receptor subunit, GEREE(p)TEEEEEEEDEN, previously proposed as the possible site of CHL interaction. Complexes were analyzed using matrix-assisted laser desorption/ionization mass spectrometry for comparison with CHL. Overall, all three analogues showed better affinity than CHL for complex formation with both the nonphosphorylated and phosphorylated epitopes.  相似文献   

13.
The substitution of aspartic acid for the naturally-occurring histidine residue in position B10 in human insulin results in an insulin analogue which displays an in vitro potency 4- to 5-fold greater than the parent compound. This substitution has been introduced into six insulin analogues which, before modification, display potencies ranging from less than 0.01-fold to 3-fold relative to natural insulin. In each case, the resulting aspartic acid-substituted analogue is substantially more potent than the parent compound. Thus, it is now possible to prepare "tailor-made" insulins with enhanced potency.  相似文献   

14.
We have synthesised an extensive series of URB602 analogues as inhibitors of monoacylglycerol lipase (MAGL), which is the major enzyme responsible for metabolising the endocannabinoid 2-arachidonylglycerol. The recently identified crystal structure of MAGL was used in the design strategy and revealed three possible binding sites for URB602 and the proposed analogues. A test series of carbamate analogues were docked into the identified sites to predict the most favourable binding location. The synthesised analogues of URB602 explored the biological effects of isosteric replacement, ring size and substitution, para substitution of the biphenyl moiety and the incorporation of a bicyclic element. The compounds were tested for their ability to inhibit human MAGL. The carbamate analogue 16 displayed the most significant inhibitory activity, reducing MAGL activity to 26% of controls at 100 μM compared to 73% for the parent compound URB602.  相似文献   

15.
Isolation and separation of rat liver cells into endothelial, Kupffer, and parenchymal cell fractions were performed at different times after injection of human 125I-acetyl low density lipoproteins (LDL). In order to minimize degradation and redistribution of the injected lipoprotein during cell isolation, a low temperature (8 degrees C) procedure was applied. Ten min after injection, isolated endothelial cells contained 5 times more acetyl-LDL apoprotein per mg of cell protein than the Kupffer cells and 31 times more than the hepatocytes. A similar relative importance of the different cell types in the uptake of acetyl-LDL was observed 30 min after injection. For studies on the in vitro interaction of endothelial and Kupffer cells with acetyl-LDL, the cells were isolated with a collagenase perfusion at 37 degrees C. Pure endothelial (greater than 95%) and purified Kupffer cells (greater than 70%) were obtained by a two-step elutriation method. It is demonstrated that the rat liver endothelial cell possesses a high affinity receptor specific for the acetyl-LDL because a 35-fold excess of unlabeled acetyl-LDL inhibits association of the labeled compound for 70%, whereas unlabeled native human LDL is ineffective. Binding to the acetyl-LDL receptor is coupled to rapid uptake and degradation of the apolipoprotein. Addition of the lysosomotropic agents chloroquine (50 microM) or NH4Cl (10 mM) resulted in more than 90% inhibition of the high affinity degradation, indicating that this occurs in the lysosomes. With the purified Kupffer cell fraction, the cell association and degradation of acetyl-LDL was at least 4 times less per mg of cell protein than with the pure endothelial cells. Although cells isolated with the cold pronase technique are also still able to bind and degrade acetyl-LDL, it appeared that 40-60% of the receptors are destroyed or inactivated during the isolation procedure. It is concluded that the rat liver endothelial cell is the main cell type responsible for acetyl-LDL uptake.  相似文献   

16.
Based on the structural similarity between the naturally occurring cyclic heptapeptides rhizonin A and ternatin, two novel analogues were designed. The synthetic analogues were assessed with regard to their fat-accumulation inhibitory effect against 3T3-L1 adipocytes, and this led to the discovery of a potent and selective fat-accumulation inhibitor compared to the parent compound rhizonin A.  相似文献   

17.
The synthesis of a series of long-chain formoterol analogues in which the terminal ether residue of the beta-phenethyl-amino-substituent has been extended beyond the methyl ether residue present in the parent compound are described. Evaluation of these analogues as beta(2)-adrenoceptor agonists was used to provide an insight into the factors controlling the magnitude and duration of receptor activation.  相似文献   

18.
The synthesis of new analogues of 1alpha,25-dihydroxyvitamin D3 containing a carbamate function at the A-ring fragment has been described using the cross-coupling approach. The carbamate group was selectively introduced at the C-3 position by regioselective enzymatic alkoxycarbonylation of A-ring enyne 3 and subsequent treatment with ammonia, amines, amino alcohols, and amino acids. Biological studies to evaluate the potency of all five of these carbamate analogues were performed and demonstrated very low binding affinity for the vitamin D receptor compared with 1alpha,25-dihydroxyvitamin D3. Moreover, all the carbamate analogues were less active than 1alpha,25-dihydroxyvitamin D3 in inhibiting cell proliferation or stimulating cell differentiation. Of all the five analogues, the 3-O-carbamoyl-1alpha,25-(OH)2-D3 analogue 10a was the most potent one in vitro. However, all investigated carbamate analogues demonstrated lower calcemic effects in vivo than the parent compound.  相似文献   

19.
Novel, metabolically stable and centrally acting TRH analogues with substituted pyridinium moieties replacing the [His(2)] residue of the endogenous peptide were prepared by solid-phase Zincke reaction. The 1,4-dihydropyridine prodrugs of these analogues obtained after reducing the pyridinium moiety were able to reach the brain and maintain a sustained concentration of the charged, degradation-resistant analogues formed after enzymatic oxidation of the prodrug, as manifested by the analeptic action measured in mice. Among the four analogues reported, compound 2a showed the highest potency and longest duration of action in reducing the pentobarbital-induced sleeping time compared to the parent TRH. No binding to the endocrine TRH-receptor was measured for 2a; thus, this compound emerged as a potent, centrally acting TRH analogue.  相似文献   

20.
Two series of analogues of the novel human mitochondrial thymidine kinase inhibitor 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine were synthesized by replacing the triphenylmethoxy moiety by a variety of substituted amines and carboxamides. In all the cases, the selectivity against the mitochondrial enzyme was either maintained or improved, and several derivatives were almost as potent as the parent compound. A molecular model was built that can account for the observed selectivities.  相似文献   

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