학술논문
Fine‐tuned photochromic sulfonylureas for optical control of beta cell Ca2+ fluxes.
Document Type
Article
Author
Source
Subject
*CALCIUM channels
*IN vitro studies
*STATISTICS
*IN vivo studies
*ANALYSIS of variance
*INSULIN secretagogues
*MICROSCOPY
*ANIMAL experimentation
*SULFONYLUREAS
*NUCLEAR magnetic resonance spectroscopy
*CELLULAR signal transduction
*DYNAMICS
*T-test (Statistics)
*ANISOTROPY
*DESCRIPTIVE statistics
*FLUORIMETRY
*RESEARCH funding
*MOLECULAR structure
*DATA analysis
*DATA analysis software
*PANCREATIC beta cells
*MICE
*PHARMACODYNAMICS
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Language
ISSN
0742-3071
Abstract
We previously developed, synthesized and tested light‐activated sulfonylureas for optical control of KATP channels and pancreatic beta cell activity in vitro and in vivo. Such technology relies on installation of azobenzene photoswitches onto the sulfonylurea backbone, affording light‐dependent isomerization, alteration in ligand affinity for SUR1 and hence KATP channel conductance. Inspired by molecular dynamics simulations and to further improve photoswitching characteristics, we set out to develop a novel push‐pull closed ring azobenzene unit, before installing this on the sulfonylurea glimepiride as a small molecule recipient. Three fine‐tuned, light‐activated sulfonylureas were synthesized, encompassing azetidine, pyrrolidine and piperidine closed rings. Azetidine‐, pyrrolidine‐ and piperidine‐based sulfonylureas all increased beta cell Ca2+‐spiking activity upon continuous blue light illumination, similarly to first generation JB253. Notably, the pyrrolidine‐based sulfonylurea showed superior switch OFF performance to JB253. As such, third generation sulfonylureas afford more precise optical control over primary pancreatic beta cells, and showcase the potential of pyrrolidine‐azobenzenes as chemical photoswitches across drug classes. [ABSTRACT FROM AUTHOR]