The Experts below are selected from a list of 39 Experts worldwide ranked by ideXlab platform
Ken Ichiro Tanaka - One of the best experts on this subject based on the ideXlab platform.
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chemical modification mediated optimisation of bronchodilatory activity of Mepenzolate a muscarinic receptor antagonist with anti inflammatory activity
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that Mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
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identification of Mepenzolate derivatives with long acting bronchodilatory activity
Frontiers in Pharmacology, 2018Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that Mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.
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superiority of pulmonary administration of Mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease
Scientific Reports, 2015Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Shota Kurotsu, Hiroshi Yamazaki, Hiroshi Watanabe, Toru MaruyamaAbstract:We recently proposed that Mepenzolate bromide (Mepenzolate) would be therapeutically effective against chronic obstructive pulmonary disease (COPD) due to its both anti-inflammatory and bronchodilatory activities. In this study, we examined the benefits and adverse effects associated with different routes of Mepenzolate administration in mice. Oral administration of Mepenzolate caused not only bronchodilation but also decreased the severity of elastase-induced pulmonary emphysema; however, compared with the intratracheal route of administration, about 5000 times higher dose was required to achieve this effect. Intravenously or intrarectally administered Mepenzolate also showed these pharmacological effects. The intratracheal route of Mepenzolate administration, but not other routes, resulted in protective effects against elastase-induced pulmonary damage and bronchodilation at a much lower dose than that which affected defecation and heart rate. These results suggest that the pulmonary route of Mepenzolate administration may be superior to other routes (oral, intravenous or intrarectal) to treat COPD patients.
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
European Respiratory Journal, 2014Co-Authors: Ken Ichiro Tanaka, Tohru MizushimaAbstract:Background and Aims: The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. Methods: The severity of pulmonary emphysema in mice was assessed by various criteria, including enlargement of airspace. Lung mechanics (elastance) and respiratory function were assessed using a computer-controlled ventilator. Results: We show that intratracheal administration or inhalation of Mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although Mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, Mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Conclusions: Based on these results, we propose that Mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.
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synthesis and biological comparison of enantiomers of Mepenzolate bromide a muscarinic receptor antagonist with bronchodilatory and anti inflammatory activities
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Kengo Hanaya, Mitsuru Shoji, Takeshi Sugai, Mitsuhito WadaAbstract:Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist Mepenzolate bromide (Mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-Mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-Mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-Mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-Mepenzolate. In vivo, the bronchodilatory activity of (R)-Mepenzolate was superior to that of (S)-Mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each Mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-Mepenzolate may have superior properties to (S)-Mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.
Yasunobu Yamashita - One of the best experts on this subject based on the ideXlab platform.
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chemical modification mediated optimisation of bronchodilatory activity of Mepenzolate a muscarinic receptor antagonist with anti inflammatory activity
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that Mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
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identification of Mepenzolate derivatives with long acting bronchodilatory activity
Frontiers in Pharmacology, 2018Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that Mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.
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superiority of pulmonary administration of Mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease
Scientific Reports, 2015Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Shota Kurotsu, Hiroshi Yamazaki, Hiroshi Watanabe, Toru MaruyamaAbstract:We recently proposed that Mepenzolate bromide (Mepenzolate) would be therapeutically effective against chronic obstructive pulmonary disease (COPD) due to its both anti-inflammatory and bronchodilatory activities. In this study, we examined the benefits and adverse effects associated with different routes of Mepenzolate administration in mice. Oral administration of Mepenzolate caused not only bronchodilation but also decreased the severity of elastase-induced pulmonary emphysema; however, compared with the intratracheal route of administration, about 5000 times higher dose was required to achieve this effect. Intravenously or intrarectally administered Mepenzolate also showed these pharmacological effects. The intratracheal route of Mepenzolate administration, but not other routes, resulted in protective effects against elastase-induced pulmonary damage and bronchodilation at a much lower dose than that which affected defecation and heart rate. These results suggest that the pulmonary route of Mepenzolate administration may be superior to other routes (oral, intravenous or intrarectal) to treat COPD patients.
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synthesis and biological comparison of enantiomers of Mepenzolate bromide a muscarinic receptor antagonist with bronchodilatory and anti inflammatory activities
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Kengo Hanaya, Mitsuru Shoji, Takeshi Sugai, Mitsuhito WadaAbstract:Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist Mepenzolate bromide (Mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-Mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-Mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-Mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-Mepenzolate. In vivo, the bronchodilatory activity of (R)-Mepenzolate was superior to that of (S)-Mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each Mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-Mepenzolate may have superior properties to (S)-Mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
Nature Communications, 2013Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Toshifumi Sugizaki, Kayoko Tahara, Kumiko Iijima, Kaoru Mogushi, Hiroshi TanakaAbstract:The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. We show that intratracheal administration or inhalation of Mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although Mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, Mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Based on these results, we propose that Mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.
Tohru Mizushima - One of the best experts on this subject based on the ideXlab platform.
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chemical modification mediated optimisation of bronchodilatory activity of Mepenzolate a muscarinic receptor antagonist with anti inflammatory activity
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that Mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
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identification of Mepenzolate derivatives with long acting bronchodilatory activity
Frontiers in Pharmacology, 2018Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that Mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
European Respiratory Journal, 2014Co-Authors: Ken Ichiro Tanaka, Tohru MizushimaAbstract:Background and Aims: The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. Methods: The severity of pulmonary emphysema in mice was assessed by various criteria, including enlargement of airspace. Lung mechanics (elastance) and respiratory function were assessed using a computer-controlled ventilator. Results: We show that intratracheal administration or inhalation of Mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although Mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, Mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Conclusions: Based on these results, we propose that Mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.
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ameliorative effect of Mepenzolate bromide against pulmonary fibrosis
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Shota Kurotsu, Ken Ichiro Tanaka, Teita Asano, Tomomi Niino, Toshifumi Sugizaki, Arata Azuma, Hidekazu Suzuki, Tohru MizushimaAbstract:Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-β1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that Mepenzolate bromide (Mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of Mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of Mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, Mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of Mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-β1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of Mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-β1 activities and its stimulatory effect on GST.
Naoki Yamakawa - One of the best experts on this subject based on the ideXlab platform.
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chemical modification mediated optimisation of bronchodilatory activity of Mepenzolate a muscarinic receptor antagonist with anti inflammatory activity
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that Mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
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identification of Mepenzolate derivatives with long acting bronchodilatory activity
Frontiers in Pharmacology, 2018Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that Mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.
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superiority of pulmonary administration of Mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease
Scientific Reports, 2015Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Shota Kurotsu, Hiroshi Yamazaki, Hiroshi Watanabe, Toru MaruyamaAbstract:We recently proposed that Mepenzolate bromide (Mepenzolate) would be therapeutically effective against chronic obstructive pulmonary disease (COPD) due to its both anti-inflammatory and bronchodilatory activities. In this study, we examined the benefits and adverse effects associated with different routes of Mepenzolate administration in mice. Oral administration of Mepenzolate caused not only bronchodilation but also decreased the severity of elastase-induced pulmonary emphysema; however, compared with the intratracheal route of administration, about 5000 times higher dose was required to achieve this effect. Intravenously or intrarectally administered Mepenzolate also showed these pharmacological effects. The intratracheal route of Mepenzolate administration, but not other routes, resulted in protective effects against elastase-induced pulmonary damage and bronchodilation at a much lower dose than that which affected defecation and heart rate. These results suggest that the pulmonary route of Mepenzolate administration may be superior to other routes (oral, intravenous or intrarectal) to treat COPD patients.
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synthesis and biological comparison of enantiomers of Mepenzolate bromide a muscarinic receptor antagonist with bronchodilatory and anti inflammatory activities
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Kengo Hanaya, Mitsuru Shoji, Takeshi Sugai, Mitsuhito WadaAbstract:Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist Mepenzolate bromide (Mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-Mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-Mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-Mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-Mepenzolate. In vivo, the bronchodilatory activity of (R)-Mepenzolate was superior to that of (S)-Mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each Mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-Mepenzolate may have superior properties to (S)-Mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
Nature Communications, 2013Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Toshifumi Sugizaki, Kayoko Tahara, Kumiko Iijima, Kaoru Mogushi, Hiroshi TanakaAbstract:The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. We show that intratracheal administration or inhalation of Mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although Mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, Mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Based on these results, we propose that Mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.
Teita Asano - One of the best experts on this subject based on the ideXlab platform.
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chemical modification mediated optimisation of bronchodilatory activity of Mepenzolate a muscarinic receptor antagonist with anti inflammatory activity
Bioorganic & Medicinal Chemistry, 2019Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that Mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
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identification of Mepenzolate derivatives with long acting bronchodilatory activity
Frontiers in Pharmacology, 2018Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Yuki Kanda, Ayaka Takafuji, Masahiro Kawahara, Mitsuko Takenaga, Yoshifumi Fukunishi, Tohru MizushimaAbstract:The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that Mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.
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superiority of pulmonary administration of Mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease
Scientific Reports, 2015Co-Authors: Ken Ichiro Tanaka, Yasunobu Yamashita, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Shota Kurotsu, Hiroshi Yamazaki, Hiroshi Watanabe, Toru MaruyamaAbstract:We recently proposed that Mepenzolate bromide (Mepenzolate) would be therapeutically effective against chronic obstructive pulmonary disease (COPD) due to its both anti-inflammatory and bronchodilatory activities. In this study, we examined the benefits and adverse effects associated with different routes of Mepenzolate administration in mice. Oral administration of Mepenzolate caused not only bronchodilation but also decreased the severity of elastase-induced pulmonary emphysema; however, compared with the intratracheal route of administration, about 5000 times higher dose was required to achieve this effect. Intravenously or intrarectally administered Mepenzolate also showed these pharmacological effects. The intratracheal route of Mepenzolate administration, but not other routes, resulted in protective effects against elastase-induced pulmonary damage and bronchodilation at a much lower dose than that which affected defecation and heart rate. These results suggest that the pulmonary route of Mepenzolate administration may be superior to other routes (oral, intravenous or intrarectal) to treat COPD patients.
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synthesis and biological comparison of enantiomers of Mepenzolate bromide a muscarinic receptor antagonist with bronchodilatory and anti inflammatory activities
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Yasunobu Yamashita, Ken Ichiro Tanaka, Teita Asano, Naoki Yamakawa, Daisuke Kobayashi, Tomoaki Ishihara, Kengo Hanaya, Mitsuru Shoji, Takeshi Sugai, Mitsuhito WadaAbstract:Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist Mepenzolate bromide (Mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-Mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-Mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-Mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-Mepenzolate. In vivo, the bronchodilatory activity of (R)-Mepenzolate was superior to that of (S)-Mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each Mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-Mepenzolate may have superior properties to (S)-Mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.
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ameliorative effect of Mepenzolate bromide against pulmonary fibrosis
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Shota Kurotsu, Ken Ichiro Tanaka, Teita Asano, Tomomi Niino, Toshifumi Sugizaki, Arata Azuma, Hidekazu Suzuki, Tohru MizushimaAbstract:Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-β1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that Mepenzolate bromide (Mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of Mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of Mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, Mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of Mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-β1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of Mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-β1 activities and its stimulatory effect on GST.