Akihiko Kiyoshi
Dainippon Sumitomo Pharma Co., Ltd.
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Featured researches published by Akihiko Kiyoshi.
ACS Medicinal Chemistry Letters | 2013
Takaaki Sumiyoshi; Takeshi Enomoto; Kentaro Takai; Yoko Takahashi; Yasuko Konishi; Yoshiharu Uruno; Kengo Tojo; Atsushi Suwa; Harumi Matsuda; Tomokazu Nakako; Mutsuko Sakai; Atsushi Kitamura; Yasuaki Uematsu; Akihiko Kiyoshi
Activation of the M1 and M4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M1 and M4 over M2, M3, and M5. Among these oxindoles, compound 1 showed high selectivity for the M1 and M4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects.
Bioorganic & Medicinal Chemistry Letters | 2014
Atsushi Suwa; Yasuko Konishi; Yoshiharu Uruno; Kentaro Takai; Tomokazu Nakako; Mutsuko Sakai; Takeshi Enomoto; Yoshiaki Ochi; Harumi Matsuda; Atsushi Kitamura; Yasuaki Uematsu; Akihiko Kiyoshi; Takaaki Sumiyoshi
We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po).
Bioorganic & Medicinal Chemistry Letters | 2013
Kentaro Takai; Yasunao Inoue; Yasuko Konishi; Atsushi Suwa; Yoshiharu Uruno; Harumi Matsuda; Tomokazu Nakako; Mutsuko Sakai; Hiroyuki Nishikawa; Gakuji Hashimoto; Takeshi Enomoto; Atsushi Kitamura; Yasuaki Uematsu; Akihiko Kiyoshi; Takaaki Sumiyoshi
We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats.
Bioorganic & Medicinal Chemistry Letters | 2014
Kentaro Takai; Yasunao Inoue; Yasuko Konishi; Atsushi Suwa; Yoshiharu Uruno; Harumi Matsuda; Tomokazu Nakako; Mutsuko Sakai; Hiroyuki Nishikawa; Gakuji Hashimoto; Takeshi Enomoto; Atsushi Kitamura; Yasuaki Uematsu; Akihiko Kiyoshi; Takaaki Sumiyoshi
We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M1 and M4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M1 and M4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.
Behavioural Brain Research | 2016
Manato Kotani; Takeshi Enomoto; Takeshi Murai; Tomokazu Nakako; Yoshihiro Iwamura; Akihiko Kiyoshi; Kenji Matsumoto; Atsushi Matsumoto; Masaru Ikejiri; Tatsuo Nakayama; Yuji Ogi; Kazuhito Ikeda
Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia.
European Journal of Pharmacology | 2018
Tadashi Tsubouchi; Takeshi Kunimatsu; Shinji Tsujimoto; Akihiko Kiyoshi; Yasunori Katsura; Seiko Oku; Kazuhiro Chihara; Yukiko Mine; Toru Yamada; Isao Shimizu; Kiyoko Bando
&NA; The pharmacological activity of DSP‐6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5‐hydroxytryptamine4 (5‐HT4) receptor agonists. DSP‐6952 had a strong affinity of Ki = 51.9 nM for 5‐HT4(b) receptor, and produced contraction in the isolated guinea pig colon with EC50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5‐HT4 receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP‐6952 showed minimal effects up to 100 &mgr;M in human ether‐a‐go‐go‐related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP‐6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP‐6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP‐6952 were completely antagonized by a 5‐HT4 receptor antagonist, and another 5‐HT4 receptor agonist, TD‐5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5‐HT4 receptor agonists, and have not been regarded as a critical issue in clinical use. DSP‐6952 did not induce contraction in the rabbit coronary artery up to 100 &mgr;M, which differed from tegaserod or sumatriptan. These results show that DSP‐6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP‐6952 is a promising GI prokinetic compound with partial 5‐HT4 receptor agonistic activity as well as a favorable cardiovascular safety profile.
Behavioural Brain Research | 2016
Manato Kotani; Akihiko Kiyoshi; Takeshi Murai; Tomokazu Nakako; Kenji Matsumoto; Atsushi Matsumoto; Masaru Ikejiri; Yuji Ogi; Kazuhito Ikeda
Gastroenterology | 2018
Tadashi Tsubouchi; Takeshi Kunimatsu; Shinji Tsujimoto; Akihiko Kiyoshi; Yasunori Katsura; Kazuhiro Chihara; Yukiko Mine; Toru Yamada; Kiyoko Bando
Journal of Pharmacological and Toxicological Methods | 2015
Kenta Watanabe; Akihiko Kiyoshi; Yasunori Katsura; Yuji Ogi; Tadashi Tsubouchi; Hitoshi Funabashi
Journal of Pharmacological and Toxicological Methods | 2011
Masafumi Yabuuchi; Atsumi Shinohara; Shinji Tsujimoto; Yuji Ogi; Akihiko Kiyoshi; Terumasa Mino