Molecular glues as potential GPCR therapeutics

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116402 - 116402

Published: June 28, 2024

Language: Английский

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Changes in Induced-Antipredation Defense Traits and Transcriptome Regulations of Daphnia magna in Response to 5-HT_1A Receptor Antagonist

Environmental Science & Technology, Journal Year: 2024, Volume and Issue: 58(17), P. 7577 - 7587

Published: April 17, 2024

The serotonin signaling system plays a crucial role in regulating the ontogeny of crustaceans. Here, we describe effects different concentrations 5-hydroxytryptamine 1A receptor antagonist (WAY-100635) on induced antipredation (

Language: Английский

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Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception

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

Published: June 8, 2024

Selective manipulation of neural circuits using optogenetics and chemogenetics holds great translational potential but requires genetic access to neurons. Here, we demonstrate a general framework for identifying tool-independent, pharmacological strategies circuit-selective modulation. We developed an economically accessible calcium imaging-based approach large-scale scans endogenous receptor-mediated activity. As testbed this approach, used the mouse locus coeruleus due combination its widespread, modular efferent circuitry wide variety endogenously expressed GPCRs. Using machine learning-based action deconvolution retrograde tracing, identified agonist cocktail that selectively inhibits medial prefrontal cortex-projecting

Language: Английский

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Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration targeted isoquinuclidines. These “natural-product-like” rare in current functionally congested, making them as receptor probes. Using modular, four-component scheme, built docked virtual over 14.6 million isoquinuclidines against both µ- κ -opioid receptors (MOR KOR, respectively). Synthesis experimental testing 18 prioritized compounds found nine with low µM affinities. Structure-based optimization low- sub- nM antagonists inverse agonists targeting receptors. Cryo-electron microscopy (cryoEM) structures illuminate origins activity on each target. In mouse behavioral studies, member series joint MOR-antagonist KOR-inverse-agonist reversed morphine-induced analgesia, phenocopying MOR-selective anti-overdose agent naloxone. Encouragingly, new molecule induced less severe opioid-induced withdrawal symptoms compared to naloxone during precipitation, did not induce conditioned-place aversion, likely reflecting reduction dysphoria due compound’s KOR-inverse agonism. The strengths weaknesses bespoke docking, for opioid polypharmacology, will be considered.

Language: Английский

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Intracellular Pocket Conformations Determine Signaling Efficacy through the μ Opioid Receptor

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

It has been challenging to determine how a ligand that binds receptor activates downstream signaling pathways and predict the strength of signaling. The challenge is compounded by functional selectivity, in which single binding can activate multiple at different levels. Spectroscopic studies show largest class cell surface receptors, 7 transmembrane receptors (7TMRs), activation associated with ligand-induced shifts equilibria intracellular pocket conformations absence transducer proteins. We hypothesized through μ opioid receptor, prototypical 7TMR, linearly proportional equilibrium probability observing receptor-ligand complex. Here, we machine learning model based on this hypothesis accurately calculates efficacy both G protein β-arrestin-2 Structural features associates are expansion, toggle switch rotation, sodium collapse. Distinct activated arrangements pockets pocket. While recent work categorized ligands as active or inactive (or partially active) affinities two conformations, our approach computes along pathways.

Language: Английский

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Delta opioid receptors engage multiple signaling cascades to differentially modulate prefrontal GABA release with input and target specificity

Cell Reports, Journal Year: 2025, Volume and Issue: 44(2), P. 115293 - 115293

Published: Feb. 1, 2025

Opioids regulate circuits associated with motivation and reward across the brain. Of opioid receptor types, delta receptors (DORs) appear to have a unique role in regulating activity of related without liability for abuse. In neocortex, DORs are expressed primarily interneurons, including parvalbumin- somatostatin-expressing interneurons that inhibit somatic dendritic compartments excitatory pyramidal cells, respectively. But how transmission from these key interneuron classes is unclear. We found inhibition using different G-protein signaling pathways both converge on presynaptic calcium channels but distinct aspects channel function. This imposes temporal filtering effects, via short-term plasticity, depend regulated. Thus, engage differential cascades depending postsynaptic target compartment, effects synaptic information transfer domains.

Language: Английский

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How Ligands Achieve Biased Signaling toward Arrestins

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

G protein-coupled receptors (GPCRs) mediate the effects of various endogenous and extracellular stimuli through multiple transducers, including heterotrimeric proteins, GPCR kinases (GRKs), arrestins. Biased signaling, which preferentially activates certain protein or GRK/arrestin signaling pathways, provides great opportunities for developing drugs with enhanced therapeutic efficacy minimized side effects. In this Review, we review studies addressing structural dynamics GPCRs bound to balanced biased ligands current consensus on how ligand–receptor interactions determine outcomes. We also examine conformational changes in when complex arrestins, GRKs, highlighting a more profound impact signal transducers receptor rearrangements compared ligands. This evidence supports idea that can be achieved promotion states by agonists stabilization specific active conformations individual transducers.

Language: Английский

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GPR37 Activation Alleviates Bone Cancer Pain via the Inhibition of Osteoclastogenesis and Neuronal Hyperexcitability

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Osteolytic bone cancer pain is a primary concern for patients with metastasis, and current therapies offer inadequate relief. The present study demonstrates that activation of the G protein‐coupled receptor 37 (GPR37) by neuroprotectin D1 (NPD1) or artesunate (ARU) alleviates both acute persistent in multiple mouse models cancer. GPR37 agonists also protect against cancer‐induced destruction. Mechanistically, NPD1 ARU binding to macrophages promotes release IL‐10, which further inhibits osteoclastogenesis. Moreover, direct dorsal root ganglion (DRG) neurons spinal horn reduces action potential firing frequency spontaneous excitatory postsynaptic currents (sEPSCs), thereby suppressing neuronal hyperexcitability. Importantly, analgesic protective effects are abolished Gpr37 −/− mice, β‐arrestin 2 identified as key mediator IL‐10 inhibition. In metastases, plasma levels endogenous negatively correlated intensity resorption marker CTX‐I. Collectively, these findings highlight therapeutic strategy alleviating through synergistic inhibition osteoclastogenesis

Language: Английский

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Biased Opioid Receptor Agonists: Balancing Analgesic Efficacy and Side-Effect Profiles

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1862 - 1862

Published: Feb. 21, 2025

Opioids are the most effective option for severe pain. However, it is well documented that side effects associated with prolonged opioid use significantly constrain dosage in clinical setting. Recently, researchers have concentrated on development of biased receptor agonists preferentially activate G protein signaling pathway over β-arrestin signaling. This approach based hypothesis mediates analgesic effects, whereas implicated adverse effects. Although certain studies demonstrated absence or inhibition can mitigate incidence recent research appears to challenge these earlier findings. In-depth investigations into signal transduction been conducted, potentially offering novel insights receptors. Consequently, this review elucidates contradictory roles reactions activation. Furthermore, a comparative analysis was conducted evaluate efficacy classic protein-biased agonists, TRV130 and PZM21, relative traditional non-biased agonist morphine. aims inform drugs optimize therapeutic safety, while minimizing greatest extent possible.

Language: Английский

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Structure-guided design of partial agonists at an opioid receptor

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 13, 2025

Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ receptor (δOR) is a promising target, as it lacks respiratory depression associated µ (µOR) agonists. However, early δOR full agonists caused seizures, limiting their clinical use. Partial may offer more controlled activation than agonists, but development has been hindered by uncertainty regarding molecular mechanism of partial agonism. Here we show that C6-Quino, bitopic ligand developed through structure-based design, acts selective agonist. Functional studies reveal C6-Quino shows differential activity at G-protein arrestin pathways interacts sodium binding pocket, confirmed cryo-EM analysis. demonstrates oral activity, analgesic in chronic models without causing δOR-related seizures µOR-related adverse effects which have limited usage recent times. This discovery outlines new strategy developing δOR-targeted provides framework optimizing signaling profiles other Class A GPCRs. δ-Opioid receptors are targets management reduced side effects. Here, authors use approach to design characterize agonist, highlighting its potential therapeutic relevance.

Language: Английский

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