Optical control of L-type Ca2+ channels using a diltiazem photoswitch

Fehrentz, Timm; Huber, Florian M. E.; Hartrampf, Nina; Bruegmann, Tobias; Frank, James A.; Fine, Nicholas H. F.; Malan, Daniela; Danzl, Johann G.; Tikhonov, Denis B.; Sumser, Martin; Sasse, Philipp; Hodson, David J.; Zhorov, Boris S.; Klöcker, Nikolaj; Trauner, Dirk

doi:10.1038/s41589-018-0090-8

Cited by 47 publications

(86 citation statements)

References 32 publications

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“…While we considered this approach for ifenprodil in our initial planning, modeling suggested success was unlikely due to the structural constraints of the binding site around the molecule aromatic rings (“azologized ifenprodil” behaved like a caged compound, data not shown). Recently, Trauner and colleagues used the former strategy very effectively for diltiazem to control L‐type calcium channels [56] . Again, this drug could be used at concentrations of at least 25 μM.…”

Section: Discussionmentioning

confidence: 99%

Photochemical Control of Drug Efficacy: A Comparison of Uncaging and Photoswitching Ifenprodil on NMDA Receptors

et al. 2021

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Ifenprodil is an important negative allosteric modulator of the N‐methyl‐D‐aspartate (NMDA) receptor. We have synthesized caged and photoswitchable derivatives of this small molecule drug. Caged ifenprodil was biologically inert before photolysis, and UV irradiation efficiently released the drug allowing selective inhibition of GluN2B‐containing NMDA receptors. Azobenzene‐modified ifenprodil, on the other hand, is inert in both its trans and cis configurations, although in silico modeling predicted the trans form to be able to bind to the receptor. The disparity in effectiveness between the two compounds reflects, in part, the inherent ability of each method in manipulating the binding properties of drugs. With appropriate structure‐activity relationship uncaging enables binary control of effector binding, whereas photoswitching using freely diffusible chromophores shifts the dose‐response curve of drug‐receptor interaction. Our data suggest that the efficacy of pharmacophores having a confined binding site such as ifenprodil can be controlled more easily by uncaging in comparison to photoswitching.

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Section: Discussionmentioning

confidence: 99%

Photochemical Control of Drug Efficacy: A Comparison of Uncaging and Photoswitching Ifenprodil on NMDA Receptors

et al. 2021

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“…PLs have been designed for a huge variety of neurotransmitter receptors and ion channels 8,17,18,48,49 ( Table 1). Examples include blockers of voltage-gated potassium 45,50,51 , sodium 52,53 and calcium 54 channels, activators of GIRK channels 55 , modulators of delayed rectifiers 56 , ATPsensitive 57 and two-pore domain 56 K + channels, activators of TRPV1 channels 58 , agonists and antagonists of ionotropic glutamate receptors (iGluRs) 44,[59][60][61][62] , agonists 11,63 and pore blockers 12 of nicotinic acetylcholine receptors (nAChRs), an agonist of adenosine receptors 64 , an antagonist of GABA A receptors 65 , and allosteric modulators of metabotropic glutamate receptors (mGluRs) [66][67][68][69][70] and of GABA A 71,72 receptors.…”

Section: Chemical Approachesmentioning

confidence: 99%

Optical control of neuronal ion channels and receptors

2019

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Light-controllable tools provide powerful means to manipulate and interrogate brain function with low invasiveness and high spatiotemporal precision. Although optogenetics permits neuronal excitation or inhibition at the network level, other technologies such as optopharmacology (also known as photopharmacology) have emerged that provide molecular level control by endowing light-sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signaling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light-sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the cross roads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential in understanding the molecular basis of brain function and behavior, with promises for future therapeutics.

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“…The team led by Fehrentz, Klӧcker and Trauner has developed a new chemical probe that, just with the use of light, controls whether L-type calcium channels are open or closed. 1 In their paper, the authors show that this small molecule works as a 'remote control' to switch on and off the influx of Ca 2+ ions and, as a result, modulates how much insulin pancreatic cells release or how fast the heart can beat.…”

Section: Marc Vendrellmentioning

confidence: 99%

A remote control for switching

Vendrell

2018

Nat Chem Biol

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Optical control of L-type Ca2+ channels using a diltiazem photoswitch

Cited by 47 publications

References 32 publications

Photochemical Control of Drug Efficacy: A Comparison of Uncaging and Photoswitching Ifenprodil on NMDA Receptors

Photochemical Control of Drug Efficacy: A Comparison of Uncaging and Photoswitching Ifenprodil on NMDA Receptors

Optical control of neuronal ion channels and receptors

A remote control for switching

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