Medicinal Chemistry and ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
J Med Chem. 2016 Jan 14;59(1):388-409. doi: 10.1021/acs.jmedchem.5b01562. Epub 2015 Dec 31.
Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer's and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.
M1 毒蕈碱型乙酰胆碱受体（M1 mAChR）的正变构调节剂（PAMs）是治疗包括阿尔茨海默病和精神分裂症在内的多种疾病相关认知障碍的有前途的策略。在此，我们报告了一类新型 M1 mAChR PAMs 的设计、合成和表征。4-苯基-2-吡啶酮系列中最活跃的化合物与参比化合物 1-（4-甲氧基苄基）-4-氧代-1,4-二氢喹啉-3-羧酸（BQCA）（1）具有相当的结合亲和力，但与乙酰胆碱的正协同作用明显改善，并保持对 M1 mAChR 的高度选择性。此外，我们的药理学特征揭示了具有广泛活性的配体，包括显示高内在效力和 PAM 活性的调节剂、没有检测到激动作用但具有强大 PAM 活性的调节剂以及显示强大变构激动作用但几乎没有调节活性的配体。因此，4-苯基-2-吡啶酮支架为进一步的先导优化提供了一个有吸引力的起点。
