| 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
|
| Resource |
| Human and Animal Cells |
Ba/F3(RCB0805) |
