Identification of a dihydropyridine scaffold that blocks ryanodine receptors

Gihan S Gunaratne; Robyn T Rebbeck; Lindsey M McGurran; Yasheng Yan; Thiago Arzua; Talia Frolkis; Daniel J Sprague; Xiaowen Bai; Razvan L Cornea; Timothy F Walseth; Jonathan S Marchant

doi:10.1016/j.isci.2021.103706

Identification of a dihydropyridine scaffold that blocks ryanodine receptors

iScience. 2021 Dec 27;25(1):103706. doi: 10.1016/j.isci.2021.103706. eCollection 2022 Jan 21.

Authors

Affiliations

¹ Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
² Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA.
³ Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

Abstract

Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca²⁺ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca²⁺ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca²⁺ signals evoked by cyclic adenosine 5'-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch "inhibitor") was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca²⁺ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway.

Keywords: Biochemistry; Cell biology; Molecular physiology; Natural product chemistry.

Abstract

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