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Synthesis of light-responsive modulators/labels of TRPC3/6-channels
- Abstract
- Novel light-responsive modulators/labels of TRPC3/6-channels
Mammalian Transient Receptor Potential (TRP) channels include six related protein
families. Members of the human TRP Canonical (TRPC) subfamily
(TRPC1/3/4/5/6/7), form channels that mediate Ca2+- and Na+-ion entry and are
expressed in many mammalian cell types to serve a broad-range of important
physiological processes. Recently, TRPC3/6 channels have been implicated in the
pathogenesis of cardiovascular disorders including heart failure, arrhythmias, and
sudden death. Consequently, TRPC channels have emerged as highly promising
targets for drug development, while, at the same time, their exact cellular function and
principles of pharmacologic modulation are still incompletely understood and require
better understanding. For this, novel strategies to experimentally control channel
function are urgently needed. These channels are endogenously controlled by plasma
membrane lipid metabolites, which are difficult to administer in most experimental
settings. Novel modulating or blocking ligands with potentially suitable selectivity for
exact experimental control of TRPC3/6 channel have just recently been reported. One
objective of this proposal is therefore the synthesis of small modulators
(inhibitors/activators) of TRPC3/6-channels that response to light, allowing the
control of biological events with unparalleled spatial and temporal precision – so
called “photoswitches” (e.g. azobenzens). Taking advantage of our experience in the
synthesis of pyrazole-based inhibitors of TRPC3/6-channels and benzimidazolonebased
activators as well as our expertise in microwave and continuous-flow
chemistry, we aim to generate and explore various photoswitchable ligands in
connection to the emerging pharmacology of TRPC3/6-channels. Another objective
of ours, involving small photoresponsive molecules, is the synthesis of photoaffinity
labels to help in the elucidation of potential ligand-binding sites in the TRPC3/6-
channels as well as on the structure elucidation of TRPC3/6-channels.
The research proposed herein is meant to become a significant contribution to
a thrilling and rapidly growing field for optoregulation of biological functions in
mammalian cells and for better understanding on the TRPC3/6-channel machinery. If
positive results are obtained, the arising pharmacology will importantly aid
investigations of the physiological and pathophysiological roles of TRPC channels,
facilitate the validation of TRPCs as potential therapeutic targets in different
channelopathies, and possibly provide foundations for drug discovery and
development.
- Keywords
- Optogenetik
- Photopharmakologie
- TRP Ionenkanäle
- Local Subprojectlead:
- Groschner Klaus
- Duration:
- 01.05.2015-31.12.2018
- Programme:
- Einzelprojekt
- Type of Research
- basic research
- MUG Research Units
- Division of Medical Physics and Biophysics
- Project results published
- > Lipid-independent control of endothelial and neuro... Chem Sci. 2019; 10(9):2837-2842
- > An optically controlled probe identifies lipid-gat... Nat Chem Biol. 2018; 14(4):396-404
- > Intensified Microwave-Assisted N-Acylation Procedu... Synlett. 2017; 28(6):695-700