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Akihiko Kiyoshi
Dainippon Sumitomo Pharma Co., Ltd.
Muscarinic acetylcholine receptor M3Muscarinic acetylcholine receptor M1AgonistMuscarinic acetylcholine receptorMuscarinic acetylcholine receptor M4
11Publications
4H-index
40Citations
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Publications 11
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Abstract The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine 4 (5-HT 4 ) receptor agonists. DSP-6952 had a strong affinity of K i = 51.9 nM for 5-HT 4(b) receptor, and produced contraction in the isolated guinea pig colon with EC 50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT 4 receptor agonists, cardiovascu...
2 CitationsSource
#1Tadashi TsubouchiH-Index: 2
#2Takeshi KunimatsuH-Index: 14
Last. Kiyoko BandoH-Index: 6
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#1Manato KotaniH-Index: 4
#2Takeshi EnomotoH-Index: 7
Last. Kazuhito IkedaH-Index: 6
view all 12 authors...
Abstract Antagonism of the dopamine D 3 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 D 2 /D 3 and serotonin 5-HT 2A receptor antagonist, highly occupies dopamine D 3 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 retrie...
4 CitationsSource
#1Manato KotaniH-Index: 4
#2Akihiko KiyoshiH-Index: 4
Last. Kazuhito IkedaH-Index: 6
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Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson’s disease and Tourette syndrome [1] ; [2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animal...
11 CitationsSource
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#1Kentaro Takai (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 5
#2Yasunao Inoue (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 3
Last. Takaaki Sumiyoshi (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 6
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We designed and synthesized novel N -substituted 7-azaindoline derivatives as selective M 1 and M 4 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 M 1 and M 4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.
4 CitationsSource
#1Atsushi Suwa (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 4
#2Yasuko Konishi (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 4
Last. Takaaki Sumiyoshi (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 6
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We designed and synthesized novel N -sulfonyl-7-azaindoline derivatives as selective M 4 muscarinic acetylcholine receptor agonists. Modification of the N -carbethoxy piperidine moiety of compound 2 , an M 4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1 , a selective M 4 mAChR agonist. Compound 1 showed a highly selective M 4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability a...
5 CitationsSource
#1Kentaro Takai (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 5
#2Yasunao Inoue (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 3
Last. Takaaki Sumiyoshi (Dainippon Sumitomo Pharma Co., Ltd.)H-Index: 6
view all 15 authors...
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.
5 CitationsSource
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 partia...
9 CitationsSource
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