Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer’s disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.

中文翻译：

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具有与阿尔茨海默病相关的治疗作用的精神质体 DYRK1A 抑制剂

Tau蛋白病、神经元萎缩和心理障碍是阿尔茨海默病等神经退行性疾病的标志，目前缺乏能够纠正这些问题的有效临床治疗方法。为了解决这些未满足的需求，我们采用合理的药物设计，将DYRK1A抑制剂和isoDMT的药效团相结合，开发出心生DYRK1A抑制剂。通过这种方法，我们发现了一种非致幻性化合物，能够促进皮质神经元生长并抑制 tau 蛋白过度磷酸化，同时还具有减轻痴呆症的生物和心理症状的潜力。总之，我们的结果表明，DYRK1A 和精神质体原药效团的杂交代表了一种有前途的策略，用于识别可能解决痴呆症的认知以及行为和心理症状的化合物。