MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring. To this end, we synthesized 24 new analogues and characterized their ability to potentiate dopamine signaling at the D1R and the closely related D5R. We identified structure–activity relationship trends for both aryl and alkyl modifications and our efforts afforded several analogues with improvements in activity. The most effective analogues demonstrated an approximately 8-fold amplification of dopamine-mediated D1R signaling. These findings advance the understanding of structural moieties underlying the activity of pyrimidone-based D1R positive allosteric modulators.

MLS1082 是一种结构新颖的基于嘧啶酮的 D1 样多巴胺受体正变构调节剂。 D1 多巴胺受体 (D1R) 信号传导的增强是治疗神经认知障碍的一种治疗策略。在这里，我们研究了 D1R 增强与 MLS1082 的两个突出结构特征（即嘧啶酮环上的N-芳基和C-烷基侧基）之间的关系。为此，我们合成了 24 个新类似物，并表征了它们增强 D1R 和密切相关的 D5R 多巴胺信号传导的能力。我们确定了芳基和烷基修饰的结构-活性关系趋势，并且我们的努力提供了几种活性改进的类似物。最有效的类似物显示多巴胺介导的 D1R 信号传导大约放大 8 倍。这些发现促进了对基于嘧啶酮的 D1R 正变构调节剂活性的结构部分的理解。