Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKIIα inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, γ-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKIIα hub domain. Herein, we report the first series of NCS-382 analogs displaying improved affinity and preserved brain permeability. Specifically, we present Ph-HTBA (1i) with enhanced mid-nanomolar affinity for the CaMKIIα binding site and a marked hub thermal stabilization effect along with a distinct CaMKIIα Trp403 flip upon binding. Moreover, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice, signified by a high Kp, uu value (0.85). Altogether, our study highlights Ph-HTBA as a promising candidate for CaMKIIα-associated pharmacological interventions and future clinical development.

中文翻译：

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探索用于 CaMKIIα 调制的 NCS-382 支架：Ph-HTBA 作为 CaMKIIα 枢纽域的新型高亲和力脑渗透稳定剂的合成、生化药理学和生物物理表征

Ca ²⁺ /钙调蛋白依赖性蛋白激酶 II α (CaMKIIα) 是一种脑相关激酶，也是治疗缺血性中风和神经退行性疾病的新兴药物靶标。尽管报道了 CaMKIIα 抑制剂，但它们的实用性受到低亚型选择性和脑通透性的限制。( E )-2-(5-Hydroxy-5,7,8,9-tetrahydro-6 H -benzo[7]annulen-6-ylidene)acetic acid (NCS-382) 在结构上与拟议的神经调节剂 γ 相关-羟基丁酸，是一种对 CaMKIIα 中心域具有选择性的脑穿透性高纳摩尔亲和力配体。在此，我们报告了第一个系列的 NCS-382 类似物，显示出改进的亲和力和保留的脑通透性。具体来说，我们提出 Ph-HTBA ( 1i) 对 CaMKIIα 结合位点具有增强的中纳摩尔亲和力和显着的中心热稳定效应以及独特的 CaMKIIα Trp403 在结合时翻转。此外，Ph-HTBA 具有良好的细胞通透性和低微粒体清除率，在小鼠全身给药后显示出脑通透性，表现为高 Kp、uu 值 (0.85)。总而言之，我们的研究强调 Ph-HTBA 作为 CaMKIIα 相关药理学干预和未来临床开发的有前途的候选者。