Three‐Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo DOI Creative Commons
Rosalba Sortino, Marina Cunquero, Gustavo Castro‐Olvera

et al.

Angewandte Chemie, Journal Year: 2023, Volume and Issue: 135(51)

Published: Oct. 12, 2023

Abstract To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration focusing as provided by infrared light multiphoton excitation, has promoted two‐photon photopharmacology optogenetics. However, three‐photon remains to demonstrated. We report the regulation of neuronal zebrafish larvae excitation a photoswitchable muscarinic agonist at 50 pM, billion‐fold lower concentration than used for uncaging, mid‐infrared 1560 nm, longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating wild‐type animals spatiotemporal precision. Computational calculations predict that azobenzene‐based ligands have high absorption cross‐section can directly pulsed light. The expansion pharmacology will deeply impact basic neurobiology neuromodulation phototherapies.

Language: Английский

Optical Approaches for Investigating Neuromodulation and G Protein–Coupled Receptor Signaling DOI Creative Commons
David J. Marcus, Michael R. Bruchas

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 75(6), P. 1119 - 1139

Published: Oct. 17, 2023

Despite the fact that roughly 40% of all US Food and Drug Administration (FDA)-approved pharmacological therapeutics target G protein–coupled receptors (GPCRs), there remains a gap in our understanding physiologic functional role these at systems level. Although heterologous expression vitro assays have revealed tremendous amount about GPCR signaling cascades, how cascades interact across cell types, tissues, organ obscure. Classic behavioral pharmacology experiments lack both temporal spatial resolution to resolve long-standing issues. Over past half century, has been concerted effort toward development optical tools for signaling. From initial ligand uncaging approaches more recent optogenetic techniques, strategies allowed researchers probe longstanding questions vivo vitro. These employed biologic interrogation everything from specific intramolecular events level spatiotemporally manner. In this review, we present historical perspective on motivation behind variety toolkits generated Here highlight used uncover distinct populations GPCRs their

Significance Statement

(GPCRs) remain one most targeted classes proteins pharmaceutical intervention, yet still limited unique effect physiology behavior discuss vast array techniques devised vivo.

Language: Английский

Citations

7
Synthesis and Pharmacological Characterization of New Photocaged Agonists for Histamine H3 and H4 Receptors DOI Creative Commons
Yang Zheng, Meichun Gao, Maikel Wijtmans

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(4), P. 536 - 536

Published: April 21, 2024

The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design synthesis suitable is a challenge for medicinal chemists. This article introduces photocaging strategy designed to modulate pharmacology histamine H3 receptors (H3R) H4 (H4R). Employing photoremovable group BODIPY as caging entity two agonist scaffolds—immepip 4-methylhistamine—for H3R H4R, respectively, we synthesized BODIPY-caged compounds, 5 (VUF25657) 6 (VUF25678), demonstrating 10–100-fold reduction in affinity their respective receptors. Notably, caged agonist, VUF25657, exhibits approximately 100-fold functional activity. photo-uncaging VUF25657 at 560 nm resulted release immepip, thereby restoring binding potency assays. approach presents promising method achieve optical control receptor pharmacology.

Language: Английский

Citations

2
A high-affinity, cis-on photoswitchable beta blocker to optically control β2-adrenergic receptors in vitro and in vivo DOI Creative Commons
Shuang Shi, Yang Zheng, Joëlle Goulding

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 226, P. 116396 - 116396

Published: June 26, 2024

This study introduces (S)-Opto-prop-2, a second-generation photoswitchable ligand designed for precise modulation of β2-adrenoceptor (β2AR). Synthesised by incorporating an azobenzene moiety with propranolol, (S)-Opto-prop-2 exhibited high PSScis (photostationary state cis isomer) percentage (∼90 %) and favourable half-life (>10 days), facilitating diverse bioassay measurements. In vitro, the cis-isomer displayed substantially higher β2AR binding affinity than trans-isomer (1000-fold), making one best GPCR (G protein-coupled receptor) ligands reported so far. Molecular docking in X-ray structure propranolol-bound followed site-directed mutagenesis studies, identified D1133.32, N3127.39 F2896.51 as crucial residues that contribute to ligand-receptor interactions at molecular level. vivo efficacy was assessed using rabbit ocular hypertension model, revealing isomer mimicked propranolol's effects reducing intraocular pressure, while trans inactive. Dynamic optical demonstrated two different cAMP bioassays live-cell confocal imaging, indicating reversible dynamic control activity new photopharmacology tool. conclusion, emerges promising light. The tool shows superior cis-on affinity, largest differences (1000-fold) between its configurations, efficacy, modulation. contributes valuable insights into evolving field photopharmacology, offering potential avenue targeted therapy β2AR-associated pathologies.

Language: Английский

Citations

2
Photo‐BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor DOI Creative Commons
Hubert Gerwe,

E. Schaller,

Rosalba Sortino

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(47)

Published: Aug. 13, 2024

Abstract The field of G protein‐coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, i.e ., photoswitchable ligands. Most developed tools have targeted Rhodopsin‐like family (Class A), largest GPCRs. However, to date, all such Class A ligands were designed act at orthosteric binding site these receptors. Herein, we report development first allosteric modulators GPCRs, target M 1 muscarinic acetylcholine receptor. presented benzyl quinolone carboxylic acid (BQCA) derivatives, Photo‐BQC is and tr ns , exhibit complementary photopharmacological behavior allow reversible control using as an external stimulus. This makes them valuable further investigate signaling a proof concept for

Language: Английский

Citations

2
Optical control of the β2-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol DOI Creative Commons
Reggie Bosma,

Nicola C. Dijon,

Yang Zheng

et al.

iScience, Journal Year: 2022, Volume and Issue: 25(9), P. 104882 - 104882

Published: Aug. 5, 2022

In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β1-AR β2-AR, applying an azologization strategy to first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced trans-cis isomerization (>94%) thermal stability (t1/2 > 10 days) cis-isomer in aqueous buffer. Upon illumination 360-nm light PSS cis , large differences binding affinities were observed at as well β2-AR. Notably, Opto-prop-2 (VUF17062) showed one largest optical shifts β2-AR (587-fold, cis-active), recorded so far photoswitches G protein-coupled receptors. We finally show broad utility a light-dependent competitive antagonist shown conformational sensor, by recruitment downstream effector proteins functional modulation isolated adult rat cardiomyocytes.

Language: Английский

Citations

10
A multi-dimensional view of context-dependent G protein-coupled receptor function DOI Creative Commons
Maria Martí-Solano

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(1), P. 13 - 20

Published: Jan. 23, 2023

G protein-coupled receptor (GPCR) family members can sense an extraordinary variety of biomolecules to activate intracellular signalling cascades that modulate key aspects cell physiology. Apart from their crucial role in maintaining homeostasis, these critical sensory and modulatory properties have made GPCRs the most successful drug target class date. However, establishing direct links between activation specific partners individual physiological outcomes is still ongoing challenge. By studying this complexity at increasing resolution through development novel biosensors high-throughput techniques, a growing number studies are revealing how function be diversified spatial, temporal or cell-specific manner. This mini-review will introduce recent examples context-dependent discuss it impact our understanding health disease, contribute search more selective, efficacious safer GPCR candidates.

Language: Английский

Citations

5
Photoswitchable Probes of Oxytocin and Vasopressin DOI Creative Commons

Ulrike Wirth,

Konstantin Raabe,

Predrag Kalaba

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(21), P. 14853 - 14865

Published: Oct. 19, 2023

Oxytocin (OT) and vasopressin (VP) are related neuropeptides that regulate many biological processes. In humans, OT VP act via four G protein-coupled receptors, OTR, V1aR, V1bR, V2R (VPRs), which associated with several disorders. To investigate the therapeutic potential of these particularly in receptor-dense areas brain, molecular probes a high temporal spatial resolution required. Such spatiotemporal can be achieved by incorporating photochromic moieties into VP. Here, we report design, synthesis, (photo)pharmacological characterization 12 OT- VP-derived photoprobes using different modification strategies. Despite OT's VP's sensitivity toward structural changes, identified two good potency photoswitch window for investigating OTR V1bR. These should value producing cutting-edge photocontrollable peptide study dynamic kinetic receptor activation processes specific regions brain.

Language: Английский

Citations

5
Design, synthesis and pharmacological characterization of the first photoswitchable small-molecule agonist for the Atypical Chemokine Receptor 3 DOI Creative Commons

Sophie Bérenger,

Justyna M. Adamska, Francesca Deflorian

et al.

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

Published: March 25, 2024

1. Abstract Photopharmacology offers the promise of optical modulation cellular signaling in a spatially and temporally controlled fashion with light-sensitive molecules. This study presents first small-molecule photoswitchable agonist for an atypical G protein-coupled receptor (GPCR), chemokine 3 (ACKR3). Inspired by known benzylpiperidine-based ACKR3 scaffold, 12 azobenzene-containing analogs were synthesized characterized their interaction ACKR3. After analysis Structure-Photochemistry Structure-Affinity Relationships (SAR), compound 3e was selected as best series. Compound can be effectively switched from its thermodynamically stable trans state to less active cis -isomer PhotoStationary State 96 %. The cis- only slowly switches back (t 1/2,37 °C = 15 days), trans- binds activates at 10-fold lower concentrations compared -isomer. demonstrates selectivity within panel receptors. Using recently published cryo-EM structures computational studies, binding mode is proposed perfectly line observed SAR loss upon photoswitching. (VUF25471) ligand GPCR will useful tool investigate role biological settings.

Language: Английский

Citations

1
Development of Photoswitchable Tethered Ligands that Target the μ‐Opioid Receptor DOI Creative Commons
Ranit Lahmy, Harald Hübner,

Daniel Lachmann

et al.

ChemMedChem, Journal Year: 2023, Volume and Issue: 18(23)

Published: Oct. 11, 2023

Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism function. Further conversion of such compounds covalent probes, as tethered (PTLs), additional advantages. These include localization PTLs binding pocket. Covalent increases local ligand concentration, improves site selectivity may improve differences between respective isomers. This work describes chemical, photophysical biochemical characterizations a variety designed target μ-opioid (μOR). were modeled on fentanyl, lead disulfide-containing agonist found covalently interact cysteine-enriched mutant this medically-relevant receptor.

Language: Английский

Citations

3
In Vivo Applications of Photoswitchable Bioactive Compounds DOI
Alexandre M. J. Gomila, Pau Gorostiza

Published: June 3, 2022

Photocontrol of biological processes with light-sensitive molecules offers great advantages for basic research and applied purposes. Cancer, infections, diseases the cardiac nervous system are fields that attracted most interest led to advanced properties. The in vivo studies reviewed this chapter aim test a clinically relevant context photopharmacology can provide high efficacy pharmacological spatiotemporal selectivity, low systemic side effects, open way novel therapies. converging progress develop caged photoswitchable drugs (including design, synthesis, chemical, characterization vitro vivo), achieve robust pre-clinical safety results, appeal investors, pharmaceutical industry, clinicians, should lead first clinical trials photopharmacology.

Language: Английский

Citations

4