New paradigms in purinergic receptor ligand discovery

Neuropharmacology, Journal Year: 2023, Volume and Issue: 230, P. 109503 - 109503

Published: March 13, 2023

Language: Английский

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Key aspects of modern GPCR drug discovery

SLAS DISCOVERY, Journal Year: 2023, Volume and Issue: 29(1), P. 1 - 22

Published: Aug. 23, 2023

Abstract

G-protein-coupled receptors (GPCRs) are the largest and most versatile cell surface receptor family with a broad repertoire of ligands functions. We've learned an enormous amount about discovering drugs this class since first GPCR was cloned expressed in 1986, such that it's now well-recognized GPCRs successful target for approved drugs. Here we take reader through drug discovery journey from to clinic, highlighting key learnings, best practices, challenges, trends insights on ultimately modulate function therapeutically patients. The future is inspiring, more desirable mechanisms new technologies enabling delivery better

Language: Английский

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Lipid Trolling to Optimize A₃ Adenosine Receptor-Positive Allosteric Modulators (PAMs)

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 12221 - 12247

Published: July 3, 2024

A

Language: Английский

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Species dependence of A3 adenosine receptor pharmacology and function

Purinergic Signalling, Journal Year: 2022, Volume and Issue: 19(3), P. 523 - 550

Published: Dec. 20, 2022

Language: Английский

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Extrahelical Binding Site for a 1H-Imidazo[4,5-c]quinolin-4-amine A₃Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7

Molecular Pharmacology, Journal Year: 2024, Volume and Issue: 105(3), P. 213 - 223

Published: Jan. 5, 2024

This study describes the localization and computational prediction of a binding site for A₃ adenosine receptor (A₃AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing pocket disparate from orthosteric that encompasses transmembrane domain (TMD) 1, TMD7, Helix (H) 8, which was predicted by molecular modeling validated mutagenesis. According to model, nearly planar 1H-imidazo[4,5-c]quinolinamine ring system lies parallel segments, inserted into aromatic cage formed π-π stacking interactions with side chains Y284^7.55 in TMD7 Y293^8.54 H8 π-NH bonding between exocyclic amine. 2-cyclohexyl group is positioned "upward" within small hydrophobic subpocket created residues TMDs 1 7, while 3,4-dichlorophenyl extends toward lipid interface. An H-bond N-1 amine heterocycle carbonyl G29^1.49 further stabilizes interaction. Molecular dynamics simulations two metastable intermediates, one resembling pose determined docking second involving transient Y293^8.54; simulations, each these intermediates converges final bound state. Structure-activity-relationships replacement either identified or endocyclic amines heteroatoms lacking donating ability were consistent hypothetical pose. Thus, we characterized 1H-imidazo[4,5-c]quinolin-4-amines data generated orthogonal methods, will aid rational design improved A₃AR modulators.

SIGNIFICANCE STATEMENT

Orthosteric agonists have advanced clinical trials inflammatory conditions, liver diseases, cancer. appeal selective activation could extend enhancers, would induce site- time-specific affected tissue. By identifying known modulators, structure-based drug discovery modalities can be enabled enhance pharmacological properties 1H-imidazo[4,5-c]quinolin-4-amine class

Language: Английский

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E. B. Hershberg Award: Taming Inflammation by Tuning Purinergic Signaling

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

ConspectusThe author presents his personal story from early contributions in purinergic receptor research to present-day structure-guided medicinal chemistry. Modulating signaling (encompassing pyrimidine nucleotides as well) and other nucleoside targets with small molecules is fruitful for identifying new directions therapeutic intervention. Purinergic encompasses four adenosine receptors, eight P2Y receptors that respond various extracellular nucleotides, trimeric P2X mainly ATP. Each organ tissue the body expresses some combination of this family cell-surface along enzymes transporters form, degrade, process native nucleotide agonists. The system responds physiological stress an organ, example by increasing energy supply or decreasing demand. are widespread on immune cells, such activation boosts response when where it needed, repel infection. In contrast, which activated later process─as stress-elevated ATP hydrolyzed locally ectonucleotidases─tend put brakes inflammation can be used correct imbalance pro- versus anti-inflammatory signals, chronic pain. Hypoxia activates immunosuppressive adenosine-A2A axis, originally formulated Sitkovsky, suppresses tumor microenvironment make a cancer more aggressive. Conversely, effects agonists have numerous applications. Modulators also show promise treating pain, metabolic disorders, inflammation. Thus, control harnessed wide range conditions, neurodegeneration autoimmune inflammatory diseases ischemia brain heart.The author's receiving American Chemical Society's top award chemistry 2023 provides opportunity summarize these developments their origins empirical probing receptor-ligand structure-activity relationship (SAR) current structure-based approaches, including conformational selectivity toward signaling. work each target began either before soon after was cloned, initial focus academic exercise use organic develop SAR target. Jacobson lab has introduced chemical probes 17 well associated regulators. Furthermore, surprisingly, conformationally constrained analogues designed inhibit non-purinergic selectively, opioid serotonin monoamine transporters. Only did applications pharmacological become apparent. largely enabled biological making definitive tool compounds available. Five laboratory (four derivatives) currently clinical trials (autoimmune liver conditions) acute (stroke, traumatic injury) conditions.

Language: Английский

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Characterization of Dual-Acting A₃ Adenosine Receptor Positive Allosteric Modulators That Preferentially Enhance Adenosine-Induced Gα_i3 and Gα_oA Isoprotein Activation

ACS Pharmacology & Translational Science, Journal Year: 2022, Volume and Issue: 5(8), P. 625 - 641

Published: July 15, 2022

The A

Language: Английский

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A2A adenosine receptor agonists, antagonists, inverse agonists and partial agonists

International review of neurobiology, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 27

Published: Jan. 1, 2023

Language: Английский

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A3 Adenosine Receptor Ligands: From Discovery to Clinical Trials

Topics in medicinal chemistry, Journal Year: 2023, Volume and Issue: unknown, P. 157 - 177

Published: Jan. 1, 2023

Language: Английский

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