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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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

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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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Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 Confers Agonist-Dependent G Protein Subtype Signaling Bias

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

Published: May 16, 2025

The mu opioid receptor (MOR) is a G protein-coupled (GPCR) and responsible for the effects of all medically used opioids. Most opioids activate inhibitory Gαi/o/z proteins through MOR, initiating signaling events that culminate in variety physiological such as analgesia, euphoria, respiratory depression. Gaining better understanding how chemical structure influences functional activation profiles protein subtypes by MOR critical disentangling multitude development safer analgesics. A recent pharmacology has been discovery positive allosteric modulators (PAMs) receptors, BMS-986122, which act at to increase potency full agonists efficacy partial agonists. Here, we utilized nanoBRET-based assay system live HEK 293T cells study pharmacological properties were uniquely affected BMS-986122 when signaled specific Gα subunits. We report differentially enhanced activity different subunits with greatest difference observed Additionally, binding affinity was significantly altered co-binding subunit. Site-directed mutagenesis experiments revealed key amino acid residue differences on Gαi/o involved differential observed. This sheds light molecular features biased both ligands proteins, may prove useful further or MOR.

Language: Английский

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Dopaminergic neuroprotective effects of inosine in MPTP-induced parkinsonian mice via brain-derived neurotrophic factor upregulation

Neuropharmacology, Journal Year: 2023, Volume and Issue: 238, P. 109652 - 109652

Published: July 6, 2023

Language: Английский

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Structure–Activity Studies of 1H-Imidazo[4,5-c]quinolin-4-amine Derivatives as A₃ Adenosine Receptor Positive Allosteric Modulators

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(22), P. 15238 - 15262

Published: Nov. 11, 2022

We previously reported 1H-imidazo[4,5-c]quinolin-4-amines as A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs). A3AR agonists, but not PAMs, are in clinical trials for inflammatory diseases and liver conditions. synthesized new analogues to distinguish 2-cyclopropyl antagonist 17 (orthosteric interaction demonstrated by binding predicted computationally) from PAMs (derivatives with large 2-alkyl/cycloalkyl/bicycloalkyl groups). PAM at a hydrophobic site on the cytosolic interface. Although having low Caco-2 permeability high plasma protein binding, 2-cyclohept-4-enyl-N-3,4-dichlorophenyl, MRS7788 18, 2-heptan-4-yl-N-4-iodophenyl, MRS8054 39, derivatives were orally bioavailable rat. 2-Heptan-4-yl-N-3,4-dichlorophenyl 14 2-cyclononyl-N-3,4-dichlorophenyl 20 39 greatly enhanced Cl-IB-MECA-stimulated [35S]GTPγS Emax, only 12b trending toward decreasing agonist EC50. A feasible route radio-iodination p-position of 4-phenylamino substituent suggests potential radioligand binding. Herein, we advanced an approach developing A3AR-activating drugs that potentially event- site-specific action.

Language: Английский

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Efeito Anti-Hipertensivo de Novos Agonistas do Receptor de Adenosina em Ratos Espontaneamente Hipertensos

Arquivos Brasileiros de Cardiologia, Journal Year: 2024, Volume and Issue: 121(2)

Published: Jan. 1, 2024

Resumo Fundamento A hipertensão arterial sistêmica é um fator de risco para disfunções cardíacas, renais e metabólicas. busca por novas estratégias prevenir tratar doenças cardiovasculares levou à síntese N-acilidrazonas produzir efeito anti-hipertensivo. Os receptores adenosina são alvo alternativo reduzir a pressão devido sua ação vasodilatadora propriedades antioxidantes, que podem o estresse oxidativo característico da sistêmica. Objetivo Avaliar perfil anti-hipertensivo novos compostos contendo selênio [...]

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First Potent Macrocyclic A₃ Adenosine Receptor Agonists Reveal G-Protein and β-Arrestin2 Signaling Preferences

ACS Pharmacology & Translational Science, Journal Year: 2023, Volume and Issue: 6(9), P. 1288 - 1305

Published: Aug. 8, 2023

(N)-Methanocarba adenosine derivatives (A3 receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N6 and C2 positions with terminal alkenes for ring closure. The resulting macrocycles of 17–20 atoms retained affinity, indicating a spatially proximal orientation these receptor-bound chains, consistent molecular modeling 12. C2-Arylethynyl-linked macrocycle 19 was more A3AR-selective than 2-ether-linked 12 (both 5′-methylamides, human (h) A3AR affinities (Ki): 22.1 25.8 nM, respectively), lower mouse affinities. Functional hA3AR comparison two sets open/closed analogues in β-arrestin2 Gi/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1. potencies 1 all three Gαi isoforms slightly less its binding affinity (Ki: 1.4 nM), while the Gαi1 Gαi2 roughly an order magnitude higher radioligand affinity. Gαi2-coupling enhanced (EC50 2.56 ∼40% greater maximal efficacy 1). Di-O-allyl precursor 18 cyclized to form 19, increasing potency by 7.5-fold. their open precursors 11 potently stimulated recruitment, EC50 values (nM) 5.17, 4.36, 1.30, 4.35, respectively, nearly 50% compared This example macrocyclization altering coupling pathways small-molecule (nonpeptide) GPCR is first potent selective macrocyclic AR agonists. These initial can serve as guide future design displaying unanticipated pharmacology.

Language: Английский

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Copper catalysis in the synthesis of N-naphthyl and N-quinolinyl derivatives of adamantane-containing amines

Russian Chemical Bulletin, Journal Year: 2023, Volume and Issue: 72(11), P. 2612 - 2623

Published: Nov. 1, 2023

Language: Английский

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