This Letter details our efforts to develop novel tricyclic M₄ PAM scaffolds with improved pharmacological properties. This endeavor involved a “tie-back” strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c′]dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M₄ receptor.

中文翻译：

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结构不同的三环 M4 正变构调节剂 (PAM) 化学型的发现——第 2 部分

这封信详细介绍了我们为开发具有改进的药理特性的新型三环 M ₄ PAM 支架所做的努力。这项努力涉及一种“回接”策略，以取代 3-amino-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide 核心，从而发现了两个新的三环核心：7,9 -二甲基吡啶并[3',2':4,5]噻吩并[3,2-d]嘧啶核和2,4-二甲基噻吩并[2,3 - b :5,4-c']联吡啶核。两个三环核心都显示出对人类 M ₄受体的低纳摩尔效力。