研究業績
ACS Chemical Neuroscience
A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation
著者
Yoshihisa Hirota, Taiki Sato, Rina Watanabe, Kazuki Takeda, Sho Sano, Satoshi Asano, Yuki Shibahashi, Yumi Yasuda, Yuta Takagi, Yutaro Yamashita, Wu YuXin, Mikino Arakawa, Yuri Maitani, Vannessa Lawai, Kurumi Nakagawa, Natsuko Furukawa, Atsuko Takeuchi, Chisato Tode, Maya Kamao, Akimori Wada, Zainab Ngaini, Yoshitomo Suhara
カテゴリ
学術論文
Abstract
Vitamin K, primarily known for its roles in coagulation and bone metabolism, has recently been implicated in neuroprotection and neuronal differentiation, particularly via its bioactive form, menaquinone-4 (MK-4). Here, we synthesized 12 vitamin K compounds with retinoic acid-conjugated side chains and methyl ester modifications to enhance neuroactive properties. Among these, compound 7 demonstrated superior stability, robust transcriptional activation via steroid and xenobiotic receptor and retinoic acid receptor, and efficient induction of neuronal differentiation in mouse neural progenitor cells. Mechanistic analyzes revealed that Vitamin K activates metabotropic glutamate receptor 1 (mGluR1). Docking simulations confirmed its stronger mGluR1-binding affinity compared to MK-4. In vivo pharmacokinetics in C57BL/6 mice showed effective blood–brain barrier penetration, with compound 7 metabolizing into MK-4 over time. These findings establish compound 7 as a promising candidate for neurodegenerative disease therapies through its unique neuroactive mechanisms.