Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor.

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. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Hiroaki Tanaka, Kenji Negoro, Takanori Koike, Issei Tsukamoto, Kazuhiro Yokoyama, Jun Maeda, Yusuke Inagaki, Yukinori Shimoshige, Katsutoshi Ino, Kenichiro Ishizu, Taisuke Takahashi. Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor. Bioorganic & medicinal chemistry. 2020 Jul 01;28(13):115531

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PMID: 32386953

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