Reference - Detail
| RRC ID | 62831 |
|---|---|
| Author | Tanaka H, Negoro K, Koike T, Tsukamoto I, Yokoyama K, Maeda J, Inagaki Y, Shimoshige Y, Ino K, Ishizu K, Takahashi T. |
| Title | Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor. |
| Journal | Bioorg Med Chem |
| Abstract |
The M3 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 M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 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 M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-preferring M3/M5 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 M3 mAChR for further investigation of its pharmacological function both in vitro and in vivo. |
| Volume | 28(13) |
| Pages | 115531 |
| Published | 2020-7-1 |
| DOI | 10.1016/j.bmc.2020.115531 |
| PII | S0968-0896(20)30357-6 |
| PMID | 32386953 |
| MeSH | Allosteric Regulation Amines / chemistry Animals CHO Cells Central Nervous System / drug effects 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 |
| IF | 3.073 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 4 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Ba/F3(RCB0805) |