Discovery and structure-activity relationships study of positive allosteric modulators of the M 3 muscarinic acetylcholine receptor
The M muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in th...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2020-07, Vol.28 (13), p.115531 |
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| creator | Tanaka, Hiroaki Negoro, Kenji Koike, Takanori Tsukamoto, Issei Yokoyama, Kazuhiro Maeda, Jun Inagaki, Yusuke Shimoshige, Yukinori Ino, Katsutoshi Ishizu, Kenichiro Takahashi, Taisuke |
| description | The M
muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M
mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M
mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M
, M
, and M
mAChRs, and moderate selectivity over the M
mAChR, indicating that compound 9 is an M
-preferring M
/M
dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M
mAChR for further investigation of its pharmacological function both in vitro and in vivo. |
| doi_str_mv | 10.1016/j.bmc.2020.115531 |
| format | Article |
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muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M
mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M
mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M
, M
, and M
mAChRs, and moderate selectivity over the M
mAChR, indicating that compound 9 is an M
-preferring M
/M
dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M
mAChR for further investigation of its pharmacological function both in vitro and in vivo.</description><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2020.115531</identifier><identifier>PMID: 32386953</identifier><language>eng</language><publisher>England</publisher><subject>Allosteric Regulation ; Amines - chemistry ; Animals ; Central Nervous System - drug effects ; CHO Cells ; Cricetulus ; Drug Evaluation, Preclinical ; High-Throughput Screening Assays ; Humans ; Muscarinic Agonists - chemical synthesis ; Muscarinic Agonists - pharmacology ; Neuroprotective Agents - chemical synthesis ; Neuroprotective Agents - pharmacokinetics ; Piperidines - chemistry ; Pyrrolidines - chemistry ; Rats ; Receptors, Muscarinic - metabolism ; Stereoisomerism ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - pharmacokinetics</subject><ispartof>Bioorganic & medicinal chemistry, 2020-07, Vol.28 (13), p.115531</ispartof><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32386953$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanaka, Hiroaki</creatorcontrib><creatorcontrib>Negoro, Kenji</creatorcontrib><creatorcontrib>Koike, Takanori</creatorcontrib><creatorcontrib>Tsukamoto, Issei</creatorcontrib><creatorcontrib>Yokoyama, Kazuhiro</creatorcontrib><creatorcontrib>Maeda, Jun</creatorcontrib><creatorcontrib>Inagaki, Yusuke</creatorcontrib><creatorcontrib>Shimoshige, Yukinori</creatorcontrib><creatorcontrib>Ino, Katsutoshi</creatorcontrib><creatorcontrib>Ishizu, Kenichiro</creatorcontrib><creatorcontrib>Takahashi, Taisuke</creatorcontrib><title>Discovery and structure-activity relationships study of positive allosteric modulators of the M 3 muscarinic acetylcholine receptor</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>The M
muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M
mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M
mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M
, M
, and M
mAChRs, and moderate selectivity over the M
mAChR, indicating that compound 9 is an M
-preferring M
/M
dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M
mAChR for further investigation of its pharmacological function both in vitro and in vivo.</description><subject>Allosteric Regulation</subject><subject>Amines - chemistry</subject><subject>Animals</subject><subject>Central Nervous System - drug effects</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Drug Evaluation, Preclinical</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Muscarinic Agonists - chemical synthesis</subject><subject>Muscarinic Agonists - pharmacology</subject><subject>Neuroprotective Agents - chemical synthesis</subject><subject>Neuroprotective Agents - pharmacokinetics</subject><subject>Piperidines - chemistry</subject><subject>Pyrrolidines - chemistry</subject><subject>Rats</subject><subject>Receptors, Muscarinic - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - pharmacokinetics</subject><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo10M1KxDAUBeAgiDOOPoAbyQt0zG2apl3K-AsjbnQ9pLcJzdA2JUkHuvbFjairyzl8nMUl5AbYFhiUd8dtM-A2Z3nKIASHM7KGoiwyzmtYkcsQjoyxvKjhgqx4zquyFnxNvh5sQHfSfqFqbGmIfsY4e50pjPZk40K97lW0bgydnUICc7tQZ-jkgk1CU9X3LkTtLdLBtXPCzocfETtN3yinwxxQeTsmoFDHpcfO9XbUaRn1lPQVOTeqD_r6727I59Pjx-4l278_v-7u99kErIqZMXnVouTABfISq6aC1ig0TDSVSQ2TQgpsGiHrutZSgBRcN6KQYFCUCviG3P7uTnMz6PYweTsovxz-v8G_AcyjZKM</recordid><startdate>20200701</startdate><enddate>20200701</enddate><creator>Tanaka, Hiroaki</creator><creator>Negoro, Kenji</creator><creator>Koike, Takanori</creator><creator>Tsukamoto, Issei</creator><creator>Yokoyama, Kazuhiro</creator><creator>Maeda, Jun</creator><creator>Inagaki, Yusuke</creator><creator>Shimoshige, Yukinori</creator><creator>Ino, Katsutoshi</creator><creator>Ishizu, Kenichiro</creator><creator>Takahashi, Taisuke</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20200701</creationdate><title>Discovery and structure-activity relationships study of positive allosteric modulators of the M 3 muscarinic acetylcholine receptor</title><author>Tanaka, Hiroaki ; Negoro, Kenji ; Koike, Takanori ; Tsukamoto, Issei ; Yokoyama, Kazuhiro ; Maeda, Jun ; Inagaki, Yusuke ; Shimoshige, Yukinori ; Ino, Katsutoshi ; Ishizu, Kenichiro ; Takahashi, Taisuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p108t-ff28dc73135c36c8b81dfacf05b8fc3607575cbb57999e751753eb5471fc56a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Allosteric Regulation</topic><topic>Amines - chemistry</topic><topic>Animals</topic><topic>Central Nervous System - drug effects</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Drug Evaluation, Preclinical</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Muscarinic Agonists - chemical synthesis</topic><topic>Muscarinic Agonists - pharmacology</topic><topic>Neuroprotective Agents - chemical synthesis</topic><topic>Neuroprotective Agents - pharmacokinetics</topic><topic>Piperidines - chemistry</topic><topic>Pyrrolidines - chemistry</topic><topic>Rats</topic><topic>Receptors, Muscarinic - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tanaka, Hiroaki</creatorcontrib><creatorcontrib>Negoro, Kenji</creatorcontrib><creatorcontrib>Koike, Takanori</creatorcontrib><creatorcontrib>Tsukamoto, Issei</creatorcontrib><creatorcontrib>Yokoyama, Kazuhiro</creatorcontrib><creatorcontrib>Maeda, Jun</creatorcontrib><creatorcontrib>Inagaki, Yusuke</creatorcontrib><creatorcontrib>Shimoshige, Yukinori</creatorcontrib><creatorcontrib>Ino, Katsutoshi</creatorcontrib><creatorcontrib>Ishizu, Kenichiro</creatorcontrib><creatorcontrib>Takahashi, Taisuke</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tanaka, Hiroaki</au><au>Negoro, Kenji</au><au>Koike, Takanori</au><au>Tsukamoto, Issei</au><au>Yokoyama, Kazuhiro</au><au>Maeda, Jun</au><au>Inagaki, Yusuke</au><au>Shimoshige, Yukinori</au><au>Ino, Katsutoshi</au><au>Ishizu, Kenichiro</au><au>Takahashi, Taisuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and structure-activity relationships study of positive allosteric modulators of the M 3 muscarinic acetylcholine receptor</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2020-07-01</date><risdate>2020</risdate><volume>28</volume><issue>13</issue><spage>115531</spage><pages>115531-</pages><eissn>1464-3391</eissn><abstract>The M
muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M
mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M
mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M
, M
, and M
mAChRs, and moderate selectivity over the M
mAChR, indicating that compound 9 is an M
-preferring M
/M
dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M
mAChR for further investigation of its pharmacological function both in vitro and in vivo.</abstract><cop>England</cop><pmid>32386953</pmid><doi>10.1016/j.bmc.2020.115531</doi></addata></record> |
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| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE |
| subjects | Allosteric Regulation Amines - chemistry Animals Central Nervous System - drug effects CHO Cells Cricetulus Drug Evaluation, Preclinical High-Throughput Screening Assays Humans Muscarinic Agonists - chemical synthesis Muscarinic Agonists - pharmacology Neuroprotective Agents - chemical synthesis Neuroprotective Agents - pharmacokinetics Piperidines - chemistry Pyrrolidines - chemistry Rats Receptors, Muscarinic - metabolism Stereoisomerism Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - pharmacokinetics |
| title | Discovery and structure-activity relationships study of positive allosteric modulators of the M 3 muscarinic acetylcholine receptor |
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