Design of Soluble Compounds for Optical Control of Tetrameric P-Loop Ion Channels DOI Creative Commons

E. D. Gataulina,

Maxim V. Nikolaev, Denis B. Tikhonov

et al.

Journal of Evolutionary Biochemistry and Physiology, Journal Year: 2024, Volume and Issue: 60(6), P. 2241 - 2254

Published: Nov. 1, 2024

Abstract The photopharmacology of ion channels is a rapidly developing area. One reason for paying special attention to the design photoswitchable ligands that control fast neurophysiological processes, and their ability be locally modulated by light very important. In channels, existing drugs are usually employed photochromic analogs through incorporation moiety. At present, compounds designed many belong superfamily so-called P-loop channels. Photoswitchable differ in activities, photosensitivity, selectivity, mechanisms action. This paper provides an overview available structures.

Language: Английский

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs DOI Creative Commons
Serena Notartomaso, Nico Antenucci, Mariacristina Mazzitelli

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 3, 2024

Abstract Knowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs identify brain region-specific role mGlu5 metabotropic glutamate receptors in control pain. Optical activation systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) receptors, cingulate, prelimbic infralimbic cortices thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment alloswitch-1, an intrinsically active receptor NAM, caused analgesia, effect was reversed by light-induced inactivation cortices, thalamus. This demonstrates that blockade medial prefrontal cortex both sufficient necessary for analgesic activity antagonists. Surprisingly, when light delivered basolateral amygdala, local JF-NP-26 reduced thresholds, whereas alloswitch-1 enhanced analgesia. Electrophysiological analysis showed increased excitatory synaptic responses pyramidal neurons evoked stimulation BLA input, decreased feedforward inhibition amygdala output BLA. Both effects were optical silencing reinstated reactivation alloswitch-1. These findings demonstrate first time neuraxis not homogenous, suggest may limit overall could explain suboptimal NAMs on human studies validate photopharmacology as tool determine ideal target sites drugs.

Language: Английский

Citations

2
A ‘double-edged’ role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs DOI Creative Commons
Serena Notartomaso, Nico Antenucci, Mariacristina Mazzitelli

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Aug. 22, 2024

We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in control pain. Optical activation systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) receptors, cingulate, prelimbic, and infralimbic cortices thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment alloswitch-1, an intrinsically active receptor NAM, caused analgesia, effect was reversed by light-induced drug inactivation prelimbic cortices, thalamus. This demonstrates that blockade medial prefrontal cortex is both sufficient necessary for analgesic activity antagonists. Surprisingly, when light delivered basolateral amygdala, local JF-NP-26 reduced thresholds, whereas alloswitch-1 enhanced analgesia. Electrophysiological analysis showed increased excitatory synaptic responses pyramidal neurons evoked stimulation presumed BLA input, decreased BLA-driven feedforward inhibition amygdala output neurons. Both effects were optical silencing reinstated reactivation alloswitch-1. These findings demonstrate first time action neuraxis not homogenous, suggest may limit overall could explain suboptimal NAMs on human studies validate photopharmacology as important tool determine ideal target sites drugs.

Language: Английский

Citations

1
WAY-262611 ameliorates the inflammatory bowel disease by activating Wnt/β-catenin pathway DOI
Baiyinzi Du,

Shudan Luo,

Xujun Zhu

et al.

In Vitro Cellular & Developmental Biology - Animal, Journal Year: 2024, Volume and Issue: 60(2), P. 128 - 138

Published: Feb. 1, 2024

Language: Английский

Citations

0
Design of Soluble Compounds for Optical Control of Tetrameric P-Loop Ion Channels DOI Creative Commons

E. D. Gataulina,

Maxim V. Nikolaev, Denis B. Tikhonov

et al.

Journal of Evolutionary Biochemistry and Physiology, Journal Year: 2024, Volume and Issue: 60(6), P. 2241 - 2254

Published: Nov. 1, 2024

Abstract The photopharmacology of ion channels is a rapidly developing area. One reason for paying special attention to the design photoswitchable ligands that control fast neurophysiological processes, and their ability be locally modulated by light very important. In channels, existing drugs are usually employed photochromic analogs through incorporation moiety. At present, compounds designed many belong superfamily so-called P-loop channels. Photoswitchable differ in activities, photosensitivity, selectivity, mechanisms action. This paper provides an overview available structures.

Language: Английский

Citations

0