In vivo metabolism and mass balance of 4-[4-fluorophenoxy]benzaldehyde semicarbazone in rats.
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The pharmacokinetics, mass balance, tissue distribution, and metabolism of Co 102862 was investigated in rats after a single oral dose. [(14)C]Co 102862 showed multiexponential pharmacokinetics in rat plasma with an extensive distribution phase. After p.o. administration (approximately 10 mg/kg), the half-lives were long for total radioactivity compared with unchanged Co 102862. Profiles of rat urine and bile suggest that Co 102862 is extensively metabolized in vivo. [(14)C]Co 102862 was extensively distributed into all tissues, with the fatty tissues and secretory glands tissues containing the highest radioactivity. Elimination of radioactivity from the tissues had an estimated half-life of 14 days. A total of 91% of the administered radioactivity was recovered in both intact and bile-duct cannulated rats over 120 and 48 h, respectively, with the majority ( approximately 74%) of the radioactivity being excreted in the urine. Approximately 10% of the total radioactivity remained in the tissues on day 5 and decreased with time to approximately 3% on day 28. Bile-duct cannulated experiments show the enterohepatic circulation is an important route of elimination and reabsorption. Six metabolites were identified in the urine and bile of which the carboxylic acid was the major metabolite. The carboxylic acid was the only metabolite found in plasma and was probably responsible for the radioactivity in the tissues. (+info)
Synthesis of isatin semicarbazones as novel anticonvulsants--role of hydrogen bonding.
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PURPOSE: A series of substituted isatin semicarbazones and related bioisosteric hydrazones were designed and synthesised to meet the structural requirements essential for anticonvulsant properties. METHODS: The structures of all synthesised compounds were confirmed by means of infrared, proton magnetic resonance spectroscopy and by elemental analyses. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES), subcutaneous metrazol (ScMet) and subcutaneous strychnine (ScSty) induced seizure methods and their neurotoxic effects were determined by rotorod test. RESULTS: A number of isatin semicarbazones exhibited significant protection after intraperitoneal administration at the dose of 100 and 300mg/kg. Some of them showed good anticonvulsant activity in MES test in rats after per oral administration at the dose of 30mg/kg. The bioisosteric hydrazone derivatives were inactive in all tests. Compound 6-chloroisatin-3- (4-bromophenyl)-semicarbazone has emerged as the most active analogue of the series showing good activity in all the three tests and was more active than phenytoin and valproic acid. CONCLUSIONS: The results evidenced the importance of hydrogen bonding and suggested a new pharmacophore model with four binding sites essential for anticonvulsant activity. (+info)
A rapid and sensitive extractive spectrophotometric determination of copper(II) in pharmaceutical and environmental samples using benzildithiosemicarbazone.
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Benzildithiosemicarbazone (BDTSC) is proposed as a sensitive and selective analytical reagent for the extractive spectrophotometric determination of copper(II). BDTSC reacts with copper(II) in the pH range 1.0-7.0 to form a yellowish complex. Beer's law is obeyed in the concentration range 0.5-0.4 microg cm(-3). The yellowish Cu(II)-BDTSC complex in chloroform shows a maximum absorbance at 380 nm, with molar absorptivity and Sandell's sensitivity values of 1.63 x 10(4) dm3 mol(-1) cm(-1) and 0.00389 microg cm(-2), respectively. A repetition of the method is checked by finding the relative standard deviation (RSD) (n = 10), which is 0.6%. The composition of the Cu(II)-BDTSC complex is established as 1:1 by slope analysis, molar ratio and Asmus' methods. An excellent linearity with a correlation coefficient value of 0.98 is obtained for the Cu(II)-BDTSC complex. The instability constant of the complex calculated from Edmond and Birnbaum's method is 7.70 x 10(-4) and that of Asmus' method is 7.66 x 10(-4), at room temperature. The method is successfully employed for the determination copper(II) in pharmaceutical and environmental samples. The reliability of the method is assured by analyzing the standard alloys (BCS 5g, 10g, 19e, 78, 32a, 207 and 179) and by inter-comparison of experimental values, using an atomic absorption spectrometer. (+info)
Synthesis and anticonvulsant activities of 4-N-substituted arylsemicarbazones.
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A series of 4-N-substituted arylsemicarbazones with increased lipophilicity were synthesized and evaluated for anticonvulsant activity. The compounds provided significant protection against maximal electroshock induced seizures (MES) and seizures indicated by sc pentetrazole administration (sc PTZ) at 300 mg/kg after 0.5 h. The compounds 8 and 4 were active in MES and sc PTZ indicated seizure. The study has shown that introduction of alkyl (ethyl) at the terminal amino group and alkoxy (methoxy) moiety at the distal aryl ring led to increased activity and decreased toxicity. (+info)
Synthesis of 4-aryl substituted semicarbazones of some terpenes as novel anticonvulsants.
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PURPOSE: A series of 4-aryl substituted semicarbazones of citral and R- (-) carvone were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. METHODS: TLC evaluated purity of synthesized compounds and their structure confirmed by infrared spectroscopy, proton magnetic resonance spectroscopy and by nitrogen estimation. All the compounds were evaluated for anticonvulsant activity by maximal electroshock (MES) and subcutaneous metrazol (ScMet) induced seizure methods and minimal motor impairment was determined by rotorod test. RESULTS: All the synthesized compounds exhibited significant protection after intraperitoneal (i.p.) administration in MES. Seventy two percent of the compounds exhibited protection in ScMet test. Some of them also showed good activity after oral administration. The results showed that anticonvulsants with cyclic and acyclic terpenoid moiety retain activity in MES as well as ScMet test. The p-fluoro aryl substituted semicarbazones emerged as the most active analogue in both cyclic and acyclic terpenes. CONCLUSION: Semicarbazones with terpenoid as the lipophilic moiety resulted in compounds with broad spectrum of anticonvulsant activity and therefore, they may be utilized for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity. The results also validated pharmacophore model with four binding sites essential for anticonvulsant activity. (+info)
V102862 (Co 102862): a potent, broad-spectrum state-dependent blocker of mammalian voltage-gated sodium channels.
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1. 4-(4-Fluorophenoxy)benzaldehyde semicarbazone (V102862) was initially described as an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy. The mechanism of action was not known. We used whole-cell patch-clamp techniques to study the effects of V102862 on native and recombinant mammalian voltage-gated Na+ channels. 2. V102862 blocked Na+ currents (I(Na)) in acutely dissociated cultured rat hippocampal neurons. Potency increased with membrane depolarization, suggesting a state-dependent mechanism of inhibition. There was no significant effect on the voltage dependence of activation of I(Na). 3. The dissociation constant for the inactivated state (K(I)) was approximately 0.6 microM, whereas the dissociation constant for the resting state (K(R)) was >15 microM. 4. The binding to inactivated channels was slow, requiring a few seconds to reach steady state at -80 mV. 5. The mechanism of inhibition was characterized in more detail using human embryonic kidney-293 cells stably expressing rat brain type IIA Na+ (rNa(v)1.2) channels, a major Na+ channel alpha subunit in rat hippocampal neurons. Similar to hippocampal neurons, V102862 was a potent state-dependent blocker of rNa(v)1.2 channels with a K(I) of approximately 0.4 microM and K(R) approximately 30 microM. V102862 binding to inactivated channels was relatively slow (k(+) approximately = 1.7 microM(-1) s(-1)). V102862 shifted the steady-state availability curve in the hyperpolarizing direction and significantly retarded recovery of Na+ channels from inactivation. 6. These results suggest that inhibition of voltage-gated Na+ channels is a major mechanism underlying the anticonvulsant properties of V102862. Moreover, understanding the biophysics of the interaction may prove to be useful in designing a new generation of potent Na+ channel blocker therapeutics. (+info)
Synthesis and evaluation of 4-substituted semicarbazones of levulinic acid for anticonvulsant activity.
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OBJECTIVE: A series of 4-aryl substituted semicarbazones of levulinic acid (4-oxo pentanoic acid) was designed and synthesized to meet the structural requirements essential for anticonvulsant activity. METHODS: All the compounds were evaluated for anticonvulsant activity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous metrazol (ScMet) induced seizure methods and minimal motor impairment was determined by rotorod test. RESULTS: A majority of the compounds exhibited significant anticonvulsant activity after intraperitoneal administration. In the present study 4-(4'-fluoro phenyl) levulinic acid semicarbazone emerged as the most active molecule, showing broad spectrum of activity with low neurotoxicity. Unsubstituted levulinic acid semicarbazone was found to be inactive in all the screens. CONCLUSION: The results obtained validate the hypothesis that presence of an aryl group near the semicarbazone moiety is essential for anticonvulsant activity. The results also indicate that the hydrophilic-hydrophobic site can accommodate hydrophilic groups. (+info)
Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide: a potent, broad-spectrum state-dependent sodium channel blocker for treating pain states.
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Voltage-gated Na(+) channels may play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na(+) channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain; however, their therapeutic utility is compromised by central nervous system side effects. We reasoned that it may be possible to gain superior control over pain states and, in particular, a better therapeutic index, by designing broad-spectrum Na(+) channel blockers with higher potency, faster onset kinetics, and greater levels of state dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analog of the state-dependent Na(+) channel blocker V102862 [4-(4-fluorophenoxy)benzaldehyde semicarbazone]. Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1 to 3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and postincisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating Rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high-potency, broad-spectrum, state-dependent Na(+) channel blockers will have clinical utility for treating neuropathic, inflammatory, and postsurgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na(+) channel blockers may lead to improved pain therapeutics. (+info)