Structural and Biophysical Mechanisms of Class C G Protein-Coupled Receptor Function

Trends in Biochemical Sciences, Journal Year: 2020, Volume and Issue: 45(12), P. 1049 - 1064

Published: Aug. 26, 2020

Language: Английский

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A fine-tuned azobenzene for enhanced photopharmacology in vivo

Cell chemical biology, Journal Year: 2021, Volume and Issue: 28(11), P. 1648 - 1663.e16

Published: March 19, 2021

Language: Английский

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In vivo photopharmacology with a caged mu opioid receptor agonist drives rapid changes in behavior

Nature Methods, Journal Year: 2023, Volume and Issue: 20(5), P. 682 - 685

Published: March 27, 2023

Language: Английский

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In vivo photopharmacology with light-activated opioid drugs

Neuron, Journal Year: 2023, Volume and Issue: 111(24), P. 3926 - 3940.e10

Published: Oct. 16, 2023

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate feasibility experimental advantages vivo photopharmacology using "caged" opioid drugs that activated light after systemic administration an inactive form. To enable bidirectional manipulations endogenous receptors vivo, developed photoactivatable oxymorphone (PhOX) naloxone (PhNX), variants mu receptor agonist antagonist naloxone. Photoactivation PhOX multiple areas produced local changes occupancy, metabolic activity, neuronal calcium neurochemical signaling, pain- reward-related behaviors. Combining photoactivation optical recording extracellular dopamine revealed adaptations sensitivity mesolimbic circuitry response chronic morphine administration. This work establishes a general framework study basis action.

Language: Английский

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Optogenetics with Atomic Precision─A Comprehensive Review of Optical Control of Protein Function through Genetic Code Expansion

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Conditional control of protein activity is important in order to elucidate the particular functions and interactions proteins, their regulators, substrates, as well impact on behavior a cell or organism. Optical provides perhaps optimal means introducing spatiotemporal over function it allows for tunable, rapid, noninvasive activation its native environment. One method optical through introduction photocaged photoswitchable noncanonical amino acids (ncAAs) genetic code expansion cells animals. Genetic incorporation photoactive ncAAs at key residues tool activation, sometimes deactivation, activity. Importantly, site can typically be rationally selected based structural, mechanistic, computational information. In this review, we comprehensively summarize applications lysine, tyrosine, cysteine, serine, histidine, glutamate, aspartate derivatives, phenylalanine analogues. The extensive diverse list proteins that have been placed under demonstrates broad applicability methodology.

Language: Английский

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International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

Pharmacological Reviews, Journal Year: 2020, Volume and Issue: 73(1), P. 521 - 569

Published: Dec. 23, 2020

Metabotropic glutamate (mGlu) receptors respond to glutamate, the major excitatory neurotransmitter in mammalian brain, mediating a modulatory role that is critical for higher-order brain functions such as learning and memory. Since first mGlu receptor was cloned 1992, eight subtypes have been identified along with many isoforms splice variants. The are transmembrane-spanning proteins belonging class C G protein–coupled family represent attractive targets multitude of central nervous system disorders. Concerted drug discovery efforts over past three decades yielded wealth pharmacological tools including subtype-selective agents competitively block or mimic actions act allosterically via distinct sites enhance inhibit activity. Herein, we review physiologic pathophysiological roles individual pleiotropic nature intracellular signal transduction arising from each. We provide comprehensive analysis vitro vivo properties prototypical commercially available orthosteric agonists antagonists well allosteric modulators, ligands entered clinical trials. Finally, highlight emerging areas research hold promise facilitate rational design highly selective receptor-targeting therapeutics future.

Significance Statement

metabotropic therapeutic range psychiatric neurological Over decades, intense diverse acting either allosterically, which enabled dissection fundamental biological process modulated by established proof concept indications. molecular pharmacology offering new avenues selectively modulate neurotransmission.

Language: Английский

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Photoswitchable Pseudoirreversible Butyrylcholinesterase Inhibitors Allow Optical Control of Inhibition in Vitro and Enable Restoration of Cognition in an Alzheimer’s Disease Mouse Model upon Irradiation

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(7), P. 3279 - 3284

Published: Feb. 9, 2022

To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable inhibitors. The compounds were able specifically influence different kinetic parameters inhibition process light. For one compound, a 10-fold difference in IC50-values (44.6 nM cis, 424 trans) vitro was translated an "all or nothing" response with complete recovery murine cognition-deficit AD model at dosages as low 0.3 mg/kg.

Language: Английский

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Photoswitchable Serotonins for Optical Control of the 5‐HT_2A Receptor**

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(18)

Published: Jan. 6, 2022

Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding spatiotemporal dynamics function. While other neuromodulatory have been successfully rendered photoswitchable, reversible photocontrol not achieved, representing a major gap GPCR photopharmacology. Herein, we develop first tools that allow such control. Azo5HT-2 shows light-dependent 5-HT2A R agonism, with greater activity cis-form. Based on docking test compound analysis, also photoswitchable orthogonal, remotely-tethered ligands (PORTLs). These BG-Azo5HTs provide rapid, reversible, repeatable optical following conjugation SNAP-tagged R. Overall, this study provides foundation broad extension photopharmacology family.

Language: Английский

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N-Methyl deuterated rhodamines for protein labelling in sensitive fluorescence microscopy

Chemical Science, Journal Year: 2022, Volume and Issue: 13(29), P. 8605 - 8617

Published: Jan. 1, 2022

Rhodamine fluorophores are setting benchmarks in fluorescence microscopy. Herein, we report the deuterium (d12) congeners of tetramethyl(silicon)rhodamine, obtained by isotopic labelling four methyl groups, show improved photophysical parameters (

Language: Английский

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The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia

Current Opinion in Pharmacology, Journal Year: 2018, Volume and Issue: 38, P. 31 - 36

Published: Feb. 1, 2018

Language: Английский

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