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

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.
PMID: 32386953 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry - April 29, 2020 Category: Chemistry Authors: Tanaka H, Negoro K, Koike T, Tsukamoto I, Yokoyama K, Maeda J, Inagaki Y, Shimoshige Y, Ino K, Ishizu K, Takahashi T Tags: Bioorg Med Chem Source Type: research