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Kamil Kuca - One of the best experts on this subject based on the ideXlab platform.
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Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors.
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Marketa Komloova, Anna Horova, Kamil Kuca, Martina Hrabinova, Martin Dolezal, Daniel Jun, Jarmila Vinšová, Kamil MusilekAbstract:Abstract Two series of non-symmetrical bisquaternary pyridinium–quinolinium and pyridinium–isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as Ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.
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Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors—implications for early Myasthenia gravis treatment
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Marketa Komloova, Kamil Musilek, Anna Horova, Ondrej Holas, Vlastimil Dohnal, Frank J. Gunn-moore, Kamil KucaAbstract:Abstract This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC50) and was compared to the chosen standards Ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than Ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π–π or π–cationic interactions.
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Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment.
European journal of medicinal chemistry, 2010Co-Authors: Kamil Musilek, Marketa Komloova, Ondrej Holas, Vlastimil Dohnal, Martina Hrabinova, Miroslav Pohanka, Florian Nachon, Martin Dolezal, Kamil KucaAbstract:Abstract Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer’s disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood–brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards Ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to Ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent π–π or π–cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed.
Kamil Musilek - One of the best experts on this subject based on the ideXlab platform.
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Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors.
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Marketa Komloova, Anna Horova, Kamil Kuca, Martina Hrabinova, Martin Dolezal, Daniel Jun, Jarmila Vinšová, Kamil MusilekAbstract:Abstract Two series of non-symmetrical bisquaternary pyridinium–quinolinium and pyridinium–isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as Ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.
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Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors—implications for early Myasthenia gravis treatment
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Marketa Komloova, Kamil Musilek, Anna Horova, Ondrej Holas, Vlastimil Dohnal, Frank J. Gunn-moore, Kamil KucaAbstract:Abstract This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC50) and was compared to the chosen standards Ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than Ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π–π or π–cationic interactions.
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Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment.
European journal of medicinal chemistry, 2010Co-Authors: Kamil Musilek, Marketa Komloova, Ondrej Holas, Vlastimil Dohnal, Martina Hrabinova, Miroslav Pohanka, Florian Nachon, Martin Dolezal, Kamil KucaAbstract:Abstract Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer’s disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood–brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards Ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to Ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent π–π or π–cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed.
Marketa Komloova - One of the best experts on this subject based on the ideXlab platform.
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Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors.
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Marketa Komloova, Anna Horova, Kamil Kuca, Martina Hrabinova, Martin Dolezal, Daniel Jun, Jarmila Vinšová, Kamil MusilekAbstract:Abstract Two series of non-symmetrical bisquaternary pyridinium–quinolinium and pyridinium–isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as Ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.
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Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors—implications for early Myasthenia gravis treatment
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Marketa Komloova, Kamil Musilek, Anna Horova, Ondrej Holas, Vlastimil Dohnal, Frank J. Gunn-moore, Kamil KucaAbstract:Abstract This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC50) and was compared to the chosen standards Ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than Ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π–π or π–cationic interactions.
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Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment.
European journal of medicinal chemistry, 2010Co-Authors: Kamil Musilek, Marketa Komloova, Ondrej Holas, Vlastimil Dohnal, Martina Hrabinova, Miroslav Pohanka, Florian Nachon, Martin Dolezal, Kamil KucaAbstract:Abstract Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer’s disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood–brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards Ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to Ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent π–π or π–cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed.
Tatsuji Iga - One of the best experts on this subject based on the ideXlab platform.
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Pharmacodynamic analysis of contractile potentiation by cholinesterase inhibitors in rats
Journal of Pharmacokinetics and Biopharmaceutics, 1996Co-Authors: Koujirou Yamamoto, Yasufumi Sawada, Tatsuji IgaAbstract:Pharmacological profiles of four cholinesterase (ChE) inhibitors: edrophonium, pyridostigmine, neostigmine, and Ambenonium after iv administration to rats were analyzed. A pharmacodynamic model was developed by considering acetylcholinesterase (AChE) inhibition, direct antagonism to the nicotinic receptor, and desensitization of the nicotinic receptor. Pharmacokinetics of these drugs are dose-independent and have similar volumes of distribution at steady state (0.4–0.6 L/kg various doses). The t_1/2 increases in the order of neostigmine, edrophonium, pyridostigmine, and Ambenonium. Inhibitory constants of ChE inhibitors to bovine erythrocyte AChE determined in vitro were 2019, 276, 26, and 3.7 nM for edrophonium, pyridostigmine, neostigmine, and Ambenonium, respectively. The effect of ChE inhibitors was monitored as the increase of developed tension of triceps muscle induced by sciatic nerve stimulation. The maximum value of contractile tension after iv administration decreased at high doses of each drug and the dose-response curves were biphasic. Time courses of plasma concentration and contractile muscle tension were modeled to estimate the association/dissociation rate constants to AChE and the nicotinic receptor, desensitization rate constant of receptor, and the dissociation constant of acetylcholine (ACh) to nicotinic receptor/basal acetylcholine level ratio ( Kd/ACh _0). The estimated Kd/ACh _0 values were not dependent on the drug. A significant correlation between inhibitory constants of ChE inhibitors to AChE estimated by in vivo pharmacodynamic analysis and those determined by an in vitro enzyme kinetic study was shown, while the relationship between dissociation constants to nicotinic receptor estimated by in vivo pharmacodynamic analysis and those measured by an in vitro binding study was not clear. Other process such as desensitisization induced by endogenous ACh, diffusion rate of drugs into the synaptic cleft, action of presynaptic receptors, etc., might contribute to the dose-effect relationship of ChE inhibitors.
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Toxicodynamic analysis of cardiac effects induced by four cholinesterase inhibitors in rats.
The Journal of pharmacy and pharmacology, 1996Co-Authors: Koujirou Yamamoto, Miho Shimizu, Hisakazu Ohtani, Masahiro Hayashi, Yasufumi Sawada, Tatsuji IgaAbstract:The cardiac effect of edrophonium (2–20 μmol kg−1), pyridostigmine (0.5-5 μmol kg−1), neostigmine (0.05-0.5 μmol kg−1) and Ambenonium (0.02-0.3 μmol kg−1) was investigated after intravenous administration to rats. For pyridostigmine and neostigmine, the heart rate decreased in a dose-dependent manner, and then gradually recovered to the basal level at about 10 min. Rapid decrease of heart rate was observed after edrophonium and Ambenonium administration, and rapid recovery to the basal level within 1 min. For Ambenonium, a dose-dependent tachycardiac response was observed. The time-course of heart rate change was analysed by the effect-compartment model. Significant correlation was observed between bradycardiac EC50 values obtained by effect-compartment model analysis and inhibitory constant (Ki) to acetylcholinesterase in-vitro, suggesting that the bradycardiac response was induced by inhibition of this enzyme and following elevation of acetylcholine concentration in the synaptic cleft. On the other hand, the tachycardiac EC50 values of edrophonium and Ambenonium based on the effect-compartment model analysis were similar to dissociation constants (Kd) of these drugs to muscarinic receptors in-vitro, suggesting that the tachycardiac activity of these drugs may be associated with antagonistic activity to postsynaptic muscarinic receptors. We conclude that, clinically, edrophonium and Ambenonium are safer drugs than pyridostigmine and neostigmine, at least as regards muscarinic side-effects, including bradycardia.
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Comparative Pharmacokinetics of Four Cholinesterase Inhibitors in Rats
Biological & pharmaceutical bulletin, 1995Co-Authors: Koujirou Yamamoto, Yasufumi Sawada, Tatsuji IgaAbstract:Pharmacokinetics of a very short-acting, a short-acting and two long-acting cholinesterase (ChE) inhibitors, edrophonium, neostigmine, pyridostigmine and Ambenonium, respectively, were compared to elucidate the major determinant of their pharmacokinetics. No dose-dependency in pharmacokinetic behavior was observed within the range of 2-10 μmol/kg for edrophonium, 0.5-2 μmol/kg for pyridostigmine, 0.1-0.5 μmol/kg for neostigmine and 0.3-3 μmol/kg for Ambenonium, respectively. Neostigmine has the shortest elimination half-life, and edrophonium, pyridostigmine and Ambenonium follow in that. Four ChE inhibitors have similar Vdss values within the range of 0.3-0.7l/kg, which is similar to the muscle/plasma concentration ratio of these drugs. The liver or kidney to plasma concentration ratio of all ChE inhibitors at 20 min after i.v. administration ranged from 5 to 15. Small distribution volumes estimated from the plasma concentration profiles may reflect the distribution to muscle and to the extracellular space of other organs/tissues, while the rapid disappearance of ChE inhibitors from plasma may reflect the concentrative uptake to the liver and kidney.
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Appearance of Tolerance in the Increase of Contractile Muscle Tension by Ambenonium in Rats
Biological & pharmaceutical bulletin, 1994Co-Authors: Koujirou Yamamoto, Yasufumi Sawada, Tatsuji IgaAbstract:The relationship between the concentration of Ambenonium (AMB), a selective and reversible acetylcholinesterase (AChE) inhibitor, in plasma and the potentiation of contractile muscle tension was investigated using a sciatic nerve-muscle preparation of rat. The developed isometric contraction was enhanced dose-dependently after i.v. administration of low doses (5-20 nmol/kg) of AMB, but the contraction was weakened when AMB was administered at high doses (100-1000nmol/kg), and the concentration-effect relationship was bell-shaped. The muscle contraction profile after 50nmol/kg administration without previous administration, with 20nmol/kg and with 50 nmol/kg administered previously were quite different from each other. These findings suggest that the potentiation of contractile muscle tension by AMB may be acutely tolerated and the concentration-effect relationship may change time-dependently.
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Sensitive determination of Ambenonium in plasma using inhibitory activity to acetylcholinesterase.
Biological & pharmaceutical bulletin, 1993Co-Authors: Koujirou Yamamoto, Yasufumi Sawada, Tatsuji IgaAbstract:A sensitive analytical method for the determination of Ambenonium, a selective acetylcholinesterase inhibitor, in plasma was developed. The procedure involves ultrafiltration to remove endogenous plasma cholinesterase, followed by colorimetric measurement of the inhibitory activity to acetylcholinesterase by the thiocholine method. Coefficient of variation of within-day triplicate analysis is less than 20% at the concentration of 5 nM. Detection limit of this method is 1 nM, which is twice lower than the most sensitive HPLC method reported previously. This assay procedure is applied to the pharmacokinetic study of Ambenonium after intravenous administration of low dose (10-20 nmol/kg) to rat. This new method is rapid and simple and makes it possible to determine the Ambenonium concentration in plasma with good accuracy.
Shohei Ogoshi - One of the best experts on this subject based on the ideXlab platform.
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Pure Red Cell Aplasia and Myasthenia Gravis with Thymoma: A Case Report and Review of the Literature
Japanese journal of clinical oncology, 1998Co-Authors: Shunji Mizobuchi, Toshiyuki Yamashiro, Yoshiki Nonami, Akira Yamamoto, Motohiko Kume, Hiroshi Nakaya, Taeko Sawada, Hirokuni Taguchi, Toshiaki Moriki, Shohei OgoshiAbstract:A case of pure red cell aplasia (PRCA), myasthenia gravis (MG) and thymoma is reported. A 70-year-old woman presented withsevere anemia. Shehadbeen diagnosed as having MG8 years earlierandhersymptoms wereadequately controlled with Ambenonium chloride. When shevisited our hospital, her hematocrit was 13.7% with a hemoglobin concentration of 4.7 g/dl and her reticulocyte counts werepersistently abnormal at 0.1 %. Although both directand indirect Coombs' testswerepositive, there wasnoevidence of hemolysis. Routine screening testsfor otheretiologies of anemia were negative. Serological tests for anti-DNA and anti-acetylcholine receptor antibodies gavepositive results. A bonemarrow examination revealed severe erythroid hypoplasia. PRCA was diagnosed and the patient was treated with periodic transfusions. A lateral view chest roentgenogram anda computed tomography scanof thethorax showed the presence of ananterior mediastinal mass which was suspected to be thymoma. The patient underwent thymothymectomy and the tumorwas diagnosed as a thymoma. Although the patient received no treatment for MG and PRCA after surgery, her hematological test results rapidly improved and she was discharged from the hospital on the 29th postoperative day. At that time, her hematocrit was 33.2%, her hemoglobin concentration was 10.0 g/dl, her peripheral reticulocyte level was 1.8% and her left partial ptosis had improved. She is doing well, 9 months after surgery. For a patient to remain in remission without treatment for PRCA and MG afterthymothymectomy is extremely rare.