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1.
Abstract— Isolated liver with a recirculating perfusate was used to study 3′-azido-3′-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 μm AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0·42 ± 0·01 (mean ± s.d.) mL min?1/10 g liver. Over the study period of 105 min, 12·7 ± 2·6% of the dose was excreted in bile and of this 95% was recovered as 3′-azido-3′-deoxy-5′-O-β-d -glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5·5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0–105 min) for 3′-amino-3′-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0–250 μm ) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane. Rats dosed intraduodenally with [3H]GAZT excreted 5·8 ± 3·3% of the GAZT dose in bile within 4 h after administration. This suggests that enterohepatic recycling is involved in AZT disposition in the rat. 相似文献
2.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(3):287-293
Although 3′‐deoxy‐3′‐[18F]fluorothymidine ([18F]FLT) is a prospective radiopharmaceutical for the imaging of proliferating tumor cell, it is difficult to prepare large amount of [18F]FLT. We herein describe the preparation of [18F]FLT in an ionic liquid, [bmim][OTf] (1‐butyl‐3‐methyl‐imidazolium trifluoromethanesulfonate). At optimized condition, [18F]fluorinationin ionic liquid with 5 µl of 1 M KHCO3 and 5 mg of the precursor yielded 61.5 ± 4.3% (n=10). Total elapsed time was about 70 min including HPLC purification. The rapid synthesis of [18F]FLT can be achieved by removing all evaporation steps. Overall radiochemical yield and radiochemical purity were 30 ± 5% and >95%, respectively. This method can use a small amount of a nitrobenzenesulfonate precursor and can be adapted for automated production. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
3.
《Journal of labelled compounds & radiopharmaceuticals》2003,46(7):669-676
New approaches to the synthesis of 3′‐azido‐3′‐deoxythymidine labelled with tritium in the heterocyclic base have been developed. With this aim, enzymatic transribosylation with [3H]thymine using the enzyme preparation from rat liver and a three‐step chemical synthesis with use of the tritium labelled precursor were studies. The enzyme preparation did not catalyse the transfer of the 3′‐azido‐3′‐deoxyribosyl fragment to the [3H]thymine residue. 5′‐O‐Benzoyl‐2,3′‐anhydrothymidine was taken as a precursor for the tritium labelling by the chemical methods. The resulting [3H]3′‐azido‐3′‐deoxythymidine was obtained with a specific radioactivity of 18.3 Ci/mmol, the tritium is located in the C‐6 position of the thymine residue. Copyright © 2003 John Wiley & Sons, Ltd. 相似文献
4.
Ooie Tsuyoshi Suzuki Hiroshi Terasaki Tetsuya Sugiyama Yuichi 《Pharmaceutical research》1996,13(4):523-527
Purpose. It is reported that the cerebrospinal fluid (CSF) to plasma unbound concentration ratio of fleroxacin at steady-state is approximately 0.5 in experimental animals. These results can be accounted for by assuming the presence of an active transport system for the efflux of this compound across the choroid plexus. In the present study, the transport system for fleroxacin was characterized in isolated rat choroid plexus.
Methods. Choroid plexus was isolated from the lateral ventricles of rats. The accumulation of [14C] fleroxacin or [3H] benzylpenicillin by the choroid plexus was examined by the centrifugal filtration method.
Results. The accumulation of [14C] fleroxacin by the rat isolated choroid plexus was significantly inhibited by metabolic inhibitors (rotenone, 30 µM and carbonyl cyanide p-trifluorometh oxyphenylhydrazone (FCCP), 100 µM) and sulfhydryl reagent (p-chloromer-curibenzenesulfonic acid (PCMBS), 100 µM). This accumulation was composed of a saturable component (Vmax = 240 pmol·min–1·µl tissue–1, Km = 664 µM) and non-saturable one (P = 0.424 min–1·µl tissue–1). Accumulation of fleroxacin was competitively inhibited by benzylpenicillin and probenecid with Ki values of 29 µM and 51 µM, respectively. These values are comparable with the Km of benzylpenicillin transport and the Ki of probenecid for the benzylpenicillin transport at the choroid plexus, respectively. Furthermore, fleroxacin inhibited competitively the accumulation of [3H] benzylpenicillin with a Ki of 384 µM, a value comparable with the Km of [14C] fleroxacin transport.
Conclusions. Fleroxacin and benzylpenicillin showed mutual competitive inhibition, suggesting that both are transported via a common transport system in the choroid plexus and are pumped out from CSF into the circulation. 相似文献
5.
The ability of [3H]5′-N-ethylcarboxamidoadenosine (NECA) to specifically bind recognition sites on intact Chinese hamster ovary (CHO) cells was examined in the present study. Saturation experiments indicated that [3H]NECA bound with moderate affinity (Kd = 400 nM) and large capacity (apparent Bmax = 3.2 pmol/105 cells) to intact CHO cells. No specific binding to these cells was observed with the A1-selective agonist 20 nM [3H]cyclohexyladenosine or with the A2-selective agonist 20 nM [3H]CGS 21680. Competition studies revealed that close structural analogs of NECA and the xanthine phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) inhibited 20 nM [3H]NECA binding with moderate affinity (IC50s 0.5–15 μM). Adenosine also showed weak activity (IC50 = 100 μM) for inhibiting [3H]NECA binding. However, a wide variety of prototypic adenosine receptor agonists and antagonists did not significantly interact with these [3H]NECA recognition sites on CHO cells. [3H]NECA binding to CHO cell membranes was not sensitive to guanine nucleotides and NECA did not stimulate cAMP formation. These results are consistent with the previously demonstrated ability of [3H]NECA to bind low affinity adenosine binding proteins (adenotin proteins), as well as, adenosine receptors in a variety of mammalian tissues. The present results further indicate that [3H]NECA selectively labels in adenotin-like recognition site on intact CHO cells in the absence of detectable binding to high affinity adenosine receptors. © 1993 Wiley-Liss, Inc. 相似文献
6.
Lutz Schweiger Stuart Craib Andrew Welch Tim A. D. Smith 《Journal of labelled compounds & radiopharmaceuticals》2007,50(13):1206-1210
In this paper, we describe the radiosynthesis of the compound (E)‐2,3′,4,5′‐tetramethoxy[2‐11C]stilbene, a potential, universal tumour positron emission tomography imaging agent. The production of (E)‐2,3′,4,5′‐tetramethoxy[2‐11C]stilbene was carried out via 11C‐methylation of (E)‐2‐(hydroxy)‐3′,4,5′‐trimethoxystilbene by using [11C]methyl trifluoromethanesulfonate ([11C]methyl triflate). (E)‐2,3′,4,5′‐tetramethoxy[2‐11C]stilbene was obtained with a radiochemical purity greater than 95% in a 20 ± 2% decay‐corrected radiochemical yield, based upon [11C]carbon dioxide. Synthesis, purification and formulation were completed on an average of 30 min following the end of bombardment (EOB). The specific radioactivity obtained was 1.9 ± 0.6 GBq/µmol at EOB. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
7.
《Journal of labelled compounds & radiopharmaceuticals》2002,45(1):79-89
The enzyme, 15,15′‐β‐carotene dioxygenase (BCDOX), facilitates the oxidation of β‐carotene to yield retinal. This is a remarkable process in which one of 11 double bonds in β‐carotene is selectively oxidized. To further probe the mechanistic aspects of BCDOX, the synthesis of all‐trans‐[10′‐3H]‐8′‐apo‐β‐carotenoic acid is reported. This compound will be used as a photoaffinity labeling reagent to probe the β‐carotene binding pocket within BCDOX. The synthesis outlines a simple and efficient route for the incorporation of tritium at the 10′ olefinic carbon of 8′‐apo‐β‐carotenoic acid. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
8.
Keykavous Parang Leonard I. Wiebe Edward E. Knaus 《The Journal of pharmacy and pharmacology》1998,50(9):989-996
The in-vivo biodistribution and pharmacokinetics in mice of 3′-azido-2′,3′-dideoxythymidine ( 1 , AZT), 2-bromomyristic acid ( 2 ) and their common prodrug, (±)-3′-azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine ( 3 ) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver. The pharmacokinetics of AZT (βt1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 ± 2.9 μmol g?1 min; CL (blood clearance) = 10.5 ± 1.1 mL min?1 kg?1) and its ester prodrug ( 3 , βt1/2 = 428.5 min; AUC = 17.3 ± 4.7 μmol g?1 min; CL = 17.6 ± 4.8 mL min?1 kg?1) were compared after intravenous injection of equimolar doses (0.3 mmol kg?1) via the tail vein of Balb/c mice (25.30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 μmol g?1) and AUC (12.3 μmol min g?1) were lower than observed after AZT administration (peak concentration 0.36 μmol g?1; AUC 29.1 μmol min g?1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 μmol g?1; respective AUCs 42.5 and 12.7 μmol min g?1). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g?1) and AUCs (2.8 compared with 1.4 μmol min g?1). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself. 相似文献
9.
《Journal of labelled compounds & radiopharmaceuticals》2003,46(3):263-272
1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐[methyl‐11C]thymine ([11C]FMAU) [11C]‐ 1 was synthesised via a palladium‐mediated Stille coupling reaction of 1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐5‐(trimethylstannyl)uracil 2 with [11C]methyl iodide in a one‐pot procedure. The reaction conditions were optimized by screening various catalysts and solvents, and by altering concentrations and reaction temperatures. The highest yield was obtained using Pd2(dba)3 and P(o‐tolyl)3 in DMF at 130°C for 5 min. Under these conditions the title compound [11C]‐ 1 was obtained in 28±5% decay‐corrected radiochemical yield calculated from [11C]methyl iodide (number of experiments=7). The radiochemical purity was >99% and the specific radioactivity was 0.1 GBq/μmol at 25 min after end of bombardment. In a typical experiment 700–800 MBq of [11C]FMAU [11C]‐ 1 was obtained starting from 6–7 GBq of [11C]methyl iodide. A mixed 11C/13C synthesis to yield [11C]‐ 1 /(13C)‐ 1 followed by 13C‐NMR analysis was used to confirm the labelling position. The labelling procedure was found to be suitable for automation. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
10.
I. Victor Ekhato Jay K. Rinehart 《Journal of labelled compounds & radiopharmaceuticals》2011,54(4):175-179
2′,3′‐Dideoxyinosine‐13C5 (ddI‐13C5) and the related 2′,3′‐dideoxyadenosine‐13C5 (ddA‐13C5) were prepared from (S)‐5‐[13C5]2,3‐dideoxyribonolactone 1 . From a batch of this starting material ddI‐13C5 was made in 27% overall yield in seven steps and ddA‐13C5 in five steps and 14% overall yield. The known synthesis of ddI‐13C5 from glucose‐13C6 took 18‐steps; therefore the present work is a substantial improvement. Copyright © 2010 John Wiley & Sons, Ltd. 相似文献
11.
《Journal of labelled compounds & radiopharmaceuticals》2002,45(10):823-829
Radio‐labelled coenzyme Q10, labelled at the 3′‐position with 14C, was synthesized starting from natural solanesol and ethyl [3‐14C] acetoacetate. The radiochemical yield was 8.0% from ethyl [3‐14C] acetoacetate. The specific radioactivity of the product was 44.8 μCi, 1.66 MBq/mg. The specific radioactivity and radiochemical purity are sufficiently high to enable us to use this labelled form of coenzyme Q10 in metabolic studies. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
12.
Patrick J. Sinko John P. Sutyak Glen D. Leesman Peidi Hu Vijaya D. Makhey Hongshi Yu Curtis L. Smith 《Biopharmaceutics & drug disposition》1997,18(8):697-710
The absolute oral and regional intestinal bioavailabilities (BAs) and pharmacokinetics (PK) of 2′, 3′-dideoxyinosine (ddI), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, were investigated in an in vivo intestinal–vascular access port (IVAP) dog model. The mean (±SD) absolute regional intestinal BAs of ddI were 49·6±8·8, 42·7±7·9, and 13·6±5·4% after the bolus administration of unbuffered solutions containing 250 mg ddI into the duodenum, ileum, and colon of IVAP beagle dogs, respectively. The BA of the orally administered Videx™ 250 mg buffered chewable tablets was 44·9±1·6%. ddI absorption and disposition PK were modeled by simultaneously fitting intravenous, oral, and intestinal plasma level versus time data using a physiologically based PK model. The region-specific apparent absorption rates followed the rank order duodenum>ileum>colon. Apparent regional in vivo intestinal permeabilities correlated well with previously determined regional permeabilities in rats. The intestinal pH was monitored using a radiotelemetric pH monitoring system since ddI is unstable in an acidic environment. While the pH was found to be lower in the duodenum and proximal jejunum (∼pH 6) than in the ileum or colon (pH≥7·0), ddI is reasonably stable across the entire pH range of the dog small intestine. These studies demonstrate that the regional reduction in ddI BA is consistent with a reported distal reduction in intestinal permeability and appears to be a significant contributing factor to the high degree of absorption variability reported for ddI. © 1997 John Wiley & Sons, Ltd. 相似文献
13.
Grazyna Weltrowska Thi M.‐D. Nguyen Carole Lemieux Nga N. Chung Peter W. Schiller 《Chemical biology & drug design》2008,72(5):337-340
Analogues of the opioid peptides H‐Tyr‐c[d ‐Cys‐Gly‐Phe(pNO2)‐d ‐Cys]NH2 (non‐selective), H‐Tyr‐d ‐Arg‐Phe‐Lys‐NH2 (μ‐selective) and dynorphin A(1‐11)‐NH2 (κ‐selective) containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr1 were synthesized. All three Bcp1‐opioid peptides retained high μ opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr1‐containing parent peptides. The cyclic peptide H‐Bcp‐c[d ‐Cys‐Gly‐Phe(pNO2)‐d ‐Cys]NH2 turned out to be an extraordinarily potent, μ‐selective opioid agonist, whereas the Bcp1‐analogue of dynorphin A(1‐11)‐NH2 displayed partial agonism at the μ receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand’s ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity. 相似文献
14.
Ashis K. Basu 《Journal of labelled compounds & radiopharmaceuticals》2013,56(8):376-381
To facilitate NMR studies and low‐level detection in biological samples by mass spectrometry, [1,3, NH2‐15N3] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine was synthesized from imidazole‐4,5‐dicarboxylic acid in 21 steps. The three 15N isotopes were introduced during the chemo‐enzymatic preparation of [1,3, NH2‐15N3]‐2′‐deoxyguanosine using an established procedure. The 15N‐labeled 2′‐deoxyguanosine was converted to a 5′‐phenylthio derivative, which allowed the 8‐5′ covalent bond formation via photochemical homolytic cleavage of the C–SPh bond. SeO2 oxidation of C‐5′ followed by sodium borohydride reduction and deprotection gave the desired product in good yield. The isotopic purity of the [1,3, NH2‐15N3] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine was in excess of 99.94 atom% based on liquid chromatography–mass spectrometry measurements. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
15.
Chaw‐Chi Chiu Yea‐Wen Chen Jiunn‐Ren Wu Young‐Tso Lin Ing‐Jun Chen Jwu‐Lai Yeh 《Drug development research》2002,55(2):104-117
A vanillylamide‐based propanolamine derivative, KMUP 880708, was first investigated both in vivo and in vitro. KMUP 880708 (0.1, 0.5, 1.0, and 2.0 mg kg–1, iv) produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. KMUP 880708 (0.1, 0.5, and 1.0 mg kg–1, iv) also markedly inhibited both the tachycardia effects induced by (–)isoproterenol and arterial pressor responses induced by phenylephrine. KMUP 880708 competitively antagonized (–)isoproterenol‐induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses on isolated guinea pig tissues. The apparent pA2 values for KMUP 880708 was 7.82 ± 0.06 in the right atria, 7.51 ± 0.13 in the left atria, and 6.31 ± 0.07 in the trachea, respectively, indicating that KMUP 880708 was selective β1‐adrenoceptor blocker. In thoracic aorta experiments, KMUP 880708 also produced a competitive antagonism of norepinephrine‐induced contraction with pA2 value of 7.92 ± 0.52, indicating that KMUP 880708 was α‐adrenoceptor antagonist. In isolated rat thoracic aorta, KMUP 880708 more potently relaxed the contractions induced by phenylephrine (10–5 M) than those by high K+ (75 mM). KMUP 880708‐induced relaxation was significantly reduced by endothelium removal and by exposure to L‐NG‐nitro arginine methyl ester (L‐NAME, 1 and 3 × 10–4 M), indomethacin (3 × 10–5 M), methylene blue (10–5 M) and 1H‐[1,2,4]oxadiazolol[4,3,‐a]quinoxalin‐1‐one (ODQ, 10–6 M). The vasorelaxant effect of KMUP 880708 on phenylephrine‐induced contraction was attenuated by the pretreatment with tetraethylammonium (TEA), glibenclamide, charybdotoxin, and apamin, but not by 4‐aminopyridine (4‐AP). In addition, KMUP 880708 inhibited phenylephrine‐induced biphasic contraction and affected the fast‐twitch phase more significantly than the slow tonic phase. In the radioligand‐binding assay, the Ki values of [3H]CGP‐12177 binding to rat ventricle and lung membranes were 15.14 and 524.81 nM, respectively, and the value of [3H]prazosin binding to rat brain membrane was 3.89 nM. The ranking order of inhibition for [3H]CGP‐12177 binding on β‐adrenoceptor was propranolol > labetalol > KMUP 880708 > atenolol, and that for [3H]prazosin binding to α‐adrenoceptor was KMUP 880708 > labetalol. In conclusion, KMUP 880708 was found to be a new generation α/β‐adrenoceptor blocker with selective β1‐adrenoceptor blocking and vascular smooth muscle relaxation activities. Furthermore, the vasodilator effect of KMUP 880708 is attributed to the release of NO or NO‐related substance from vascular endothelium. While the endothelium‐independent mechanism involved in the relaxation of KMUP 880708 is probably linked to K+ channel activation in these vessels. Drug Dev. Res. 55:104–117, 2002. © 2002 Wiley‐Liss, Inc. 相似文献
16.
《Journal of labelled compounds & radiopharmaceuticals》2002,45(8):647-664
Carboxylic acid derivatives of the amyloid‐binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid‐imaging agents. A neutral amyloid probe, (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl)benzene ( 3 ), devoid of any carboxylate groups has been designed and synthesized via a 12‐step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C‐11 via [11C]methyl iodide ([11C]CH3I) methylation of a symmetric 4,4′‐dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post‐mortem AD brain, and exhibited good binding affinity (Ki=38±8 nM) for Aβ(1–40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [11C] 3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [11C] 3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR‐beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
17.
Jhy‐Chong Liang Jwu‐Lai Yeh Lien‐Chai Chiang Yu‐Chiao Yang Sheng‐Hsiung Sheu Wen‐Ter Lai Ing‐Jun Chen 《Drug development research》2000,49(2):94-108
The combination of β‐adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol‐A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol‐A (0.1–1.0 mg/kg) produced dose‐dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)‐induced hypotensive and reflex tachycardia activities in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐A also inhibited phenylephrine (20 μg/kg, i.v.)‐induced hypertensive and (‐)isoprenaline (0.5 μg/kg, i.v.)‐induced tachycardia effects. Oral administration of labedipinedilol‐A (5–50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol‐A (10–7–10–5 M) competitively antagonized (‐)isoprenaline (10–10–10–4M)‐induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol‐A also prevented the rate‐increasing effects of increased extracellular Ca2+ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐A competitively antagonized CaCl2 and norepinephrine‐induced contractions with pKCa–1 and pA2 values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K+‐induced vasocontraction. Furthermore, labedipinedilol‐A, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐A (10–9–10–6 M). The binding characteristics of labedipinedilol‐A were evaluated in [3H]CGP‐12177 binding to ventricle and lung and [3H]nitrendipine and [3H]prazosin binding to brain membranes in rats. The ‐logIC50 values of labedipinedilol‐A for β1‐, β2‐, and α1‐adrenoceptor and calcium channel, were 8.17 × 10–7 M, 8.20 × 10–7 M, 2.20 × 10–8 M, and 2.46 × 10–8 M, respectively. Labedipinedilol‐A‐induced sustained depressor effect was mainly attributed to its calcium entry and α‐adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β‐adrenoceptor and calcium entry blocking, which deleted the sympathetic activation‐associated reflex tachycardia in the heart. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley‐Liss, Inc. 相似文献
18.
Jwu‐Lai Yeh Tzu‐Hsin Yang Jhy‐Chong Liang Yeun‐Chih Huang Yi‐Ching Lo Jiunn‐Ren Wu Young‐Tso Lin Ing‐Jun Chen 《Drug development research》2000,51(1):29-42
Isoeugenodilol, derived from isoeugenol, was investigated under in vivo and in vitro conditions. Isoeugenodilol (0.1, 0.5, 1.0, and 3.0 mg kg–1, i.v.) produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. Isoeugenodilol (0.5 mg kg–1, i.v.) also markedly inhibited both the tachycardia effects induced by (‐) isoproterenol and arterial pressor responses induced by phenylephrine. A single oral administration of isoeugenodilol at doses of 10, 30, and 100 mg kg–1 dose‐dependently reduced blood pressure, with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat right atria, left atria, and guinea pig tracheal strips, isoeugenodilol competitively antagonized the (‐) isoproterenol‐induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curve of (‐) isoproterenol suggested that isoeugenodilol was a β1/β2‐adrenoceptor competitive antagonist. The apparent pA2 values were 7.33 ± 0.12 in the right atria, 7.80 ± 0.09 in the left atria, and 7.26 ± 0.11 in the trachea, indicating that isoeugenodilol was a nonselective β‐adrenoceptor blocker. In thoracic aorta experiments, isoeugenodilol also produced a competitive antagonism of norepinephrine‐induced contraction with a pA2 value of 7.47 ± 0.45. In isolated atria of reserpinized rats, cumulative additions of isoeugenodilol and propranolol produced significantly cardiodepressant responses at high concentrations (10–5 M) and were without intrinsic sympathomimetic activity (ISA). In isolated rat thoracic aorta, isoeugenodilol more potently relaxed the contractions induced by norepinephrine (3 × 10–6 M) than those by high K+ (75 mM). The vasorelaxant effects of isoeugenodilol on norepinephrine‐induced contractions were attenuated by pretreatment with tetraethylammonium (TEA) and glibenclamide, implying the involvement of K+ channel opening. In addition, isoeugenodilol inhibited norepinephrine‐induced biphasic contraction; it affected the fast phase significantly more than the slow phase. Furthermore, the binding characteristics of isoeugenodilol and various β‐adrenoceptor antagonists were evaluated in [3H]CGP‐12177 binding to rat ventricle and lung tissues and [3H]prazosin binding to brain membranes. The ranking order of inhibition for [3H]CGP‐12177 binding on β‐adrenoceptor was propranolol > labetalol > isoeugenodilol, and that for [3H]prazosin binding to α‐adrenoceptors was isoeugenodilol > labetalol. Furthermore, isoeugenodilol inhibited lipid peroxidation induced by Fe2+ and ascorbic acid with IC50 of 0.74 ± 0.03 mM, indicating that it possesses the antioxidant activity inherent in isoeugenol. In conclusion, isoeugenodilol was found to be a new generation α/β‐adrenoceptor antagonist with vasorelaxant activity by inhibiting Ca2+ channel, receptor‐mediated Ca2+ mobilization and by K+ channel opening, and to have additional potentially antioxidant effects. Drug Dev. Res. 51:29–42, 2000. © 2000 Wiley‐Liss, Inc. 相似文献
19.
《Journal of labelled compounds & radiopharmaceuticals》2002,45(1):19-28
Unprotected deoxyadenosine 1 was treated with an excess of phosphorus acid and stoichiometric proportions of N, N′‐di‐p‐tolylcarbodiimide in anhydrous pyridine to give deoxyadenosine‐5′‐monophosphite 2 . The latter was activated with trimethylsilyl chloride followed by sulphurisation with elemental 35S (specific activity>1000 Ci/mmol) in toluene solution to give deoxyadenosine‐5′‐(35S)‐thiomonophosphate [dAMP(35S)] 3 . Enzymatic conversion of deoxyadenosine‐5′‐(35S)‐thiomonophosphate to Sp‐deoxyadenosine‐5′‐(α‐35S)‐thiotriphosphate [Sp‐dATP (α‐35S)] 5 was carried out following a standard reaction protocol. Copyright © 2001 John Wiley & Sons, Ltd. 相似文献
20.
Jwu‐Lai Yeh Chieh‐Ho Tsai Jhy‐Chong Liang Jiunn‐Ren Wu Yeun‐Chih Huang Ing‐Jun Chen 《Drug development research》2001,52(3):462-474
The pharmacological properties of labedipinedilol‐B {N‐[4‐[2‐hydroxy‐3‐(2‐methoxy‐1‐oxyethylaminobenzene) propoxy]‐benzyl]‐2,6‐dimethyl‐3,5‐dicarbomethoxy‐1,4‐dihydropyridine} were investigated in vivo and in vitro in comparison with labedipinedilol‐A. Intravenous labedipinedilol‐B (0.5, 1.0, and 3.0 mg kg–1), produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐B (1.0 mg kg–1, iv) also inhibited phenylephrine (10 μg kg–1)‐induced hypertensive and (–)isoproterenol (0.5 μg kg–1)‐induced tachycardia effects. In the isolated Wistar rat right and left atria and guinea pigs tracheal strips experiments, labedipinedilol‐B (10–7, 10–6, and 10–5 M) competitively antagonized the (–)isoproterenol‐induced positive chronotropic and inotropic effects and tracheal relaxation responses in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curve of (–)isoproterenol suggested that labedipinedilol‐B was a β1/β2‐adrenoceptor competitive antagonist. Labedipinedilol‐B (10–7, 10–6, and 10–5 M) also prevented the rate‐increasing effects of increased extracellular Ca2+ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐B (10–7, 10–6, and 10–5 M) competitively antagonized the CaCl2 and norepinephrine‐induced contractions with pKCa–1 and pA2 values of 8.02 ± 0.04 and 7.55 ± 0.05 in a concentration‐dependent manner. The parallel shift to the right of the concentration–response curves of norepinephrine suggested that labedipinedilol‐B was an α‐adrenoceptor competitive antagonist. Furthermore, labedipinedilol‐B, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the isolated rat aorta, labedipinedilol‐B also competitively antagonized CaCl2‐induced contractions and made the parallel shift to the right of the concentration–response curve of CaCl2. In cultured blood vessel smooth muscle cells (A7r5 cell lines), Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐B, suggesting that the compound was a calcium channel blocker. The binding characteristics of labedipinedilol‐B were evaluated in [3H]CGP‐12177 binding to ventricle and lung and [3H]prazosin binding to brain membranes in rats. Labedipinedilol‐B also was evaluated in [3H]nitrendipine binding to brain membranes in rats. These results indicated that labedipinedilol‐B, similar to labedipinedilol‐A, has α‐adrenoceptor blocking, β‐adrenoceptor blocking, and calcium entry blocking activities in a single compound. We suggest that these two compounds represent a new generation of 1,4‐dihydropyridine‐type calcium channel blockers. Drug Dev. Res. 52:462–474, 2001. © 2001 Wiley‐Liss, Inc. 相似文献