Tanaka, Hiroaki; Negoro, Kenji; Koike, Takanori; Tsukamoto, Issei; Yokoyama, Kazuhiro; Maeda, Jun; Inagaki, Yusuke; Shimoshige, Yukinori; Ino, Katsutoshi; Ishizu, Kenichiro; Takahashi, Taisuke published the artcile< Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor>, Reference of 623-50-7 , the main research area is muscle contraction mAChR PAMs SAR HTS pharmacokinetics allosteric enhancers; Allosteric enhancers; M(3) muscarinic acetylcholine receptor; Positive allosteric modulators.
The M3 muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiol. 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 pos. allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9(I) 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 chem. probe for the M3 mAChR for further investigation of its pharmacol. function both in vitro and in vivo.
Bioorganic & Medicinal Chemistry published new progress about High-throughput screening. 623-50-7 belongs to class esters-buliding-blocks, and the molecular formula is C4H8O3, Reference of 623-50-7 .
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