Development of novel photochemical tools to regulate wakefulness

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14352
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Tsuyoshi Saitoh 筑波大学, 国際統合睡眠医科学研究機構, 助教 (80609933)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: オレキシン / 光ケージド薬物 / 睡眠覚醒 / 光反応

Outline of Final Research Achievements

The development of novel photochemical tools that selectively activate orexin receptors, which physiologically regulate sleep/wakefulness was conducted. As a method for imparting photo-responsiveness to a drug, a photo caging method that can release a drug via covalent bond cleavage by photo-irradiation was adopted. Through the structure-activity relationship study of drug candidates including originally developed OX2R agonists, a candidate drug for caging and its modifiable residue were identified. The inactivated photo-responsive OX2R agonists were synthesized by conjugating a photo-caging group. Photo-irradiation experiments using the synthetic molecules revealed that OX2R agonist was released after the photo-irradiation, and electrophysiological experiments also confirmed the response resulting from OX2R activation after photo-irradiation.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

私たちが睡眠から覚醒に移行する際、どういう分子メカニズムで起きているのか、まだ誰も明らかにしていない。この謎をひもとくためには、覚醒の誘導、維持に重要な役割を果たすオレキシン受容体の機能を時空間解像度高く正確に制御する必要がある。本研究成果は、光という外部刺激によりオレキシン受容体の機能のみを時空間選択的に制御する分子の実現可能性を示すものである。