2-Amino-5-arylethynyl-thiophen-3-yl-(phenyl)methanones as A1 Adenosine Receptor Positive Allosteric Modulators DOI
Paola Oliva,

R. Rama Suresh,

Silvia Pasquini

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(12), P. 1640 - 1646

Published: Nov. 13, 2023

A1 adenosine receptor (A1AR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure–activity relationship of 5-arylethynyl aminothiophenes as A1AR positive allosteric modulators (PAMs). The derivatives were compared in binding functional assays at human A1AR, indicating that some fluoro-substituted analogues enhanced PAM activity. identified substitution terminal phenyl ring 12 (2-F-Ph), 15 (3,4-F2-Ph, MRS7935), 21 (2-CF3-Ph) particularly enhancing was also shown to act an ago-PAM with EC50 ≈ 2 μM, without activity (30 μM) ARs. Molecular modeling indicated both 4-neopentyl groups are located a region outside transmembrane helix bundle is contact phospholipid bilayer, consistent preference for nonpolar aryl moiety. Although they hydrophobic, these PAMs could provide potential drug candidate molecules engaging protective A1ARs.

Language: Английский

Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs) DOI
Balaram Pradhan, Matteo Pavan, Courtney Fisher

et al.

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

Published: July 3, 2024

A

Language: Английский

Citations

5
Selective modulation of epileptic tissue by an adenosine A3 receptor‐activating drug DOI Creative Commons
Anwesha Ghosh, Leonor Ribeiro‐Rodrigues, Gabriele Ruffolo

et al.

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(24), P. 5041 - 5061

Published: Sept. 19, 2024

Abstract Background and Purpose Adenosine, through the A 1 receptor (A R), is an endogenous anticonvulsant. The development of adenosine agonists as antiseizure medications has been hampered by their cardiac side effects. moderately R‐selective agonist, MRS5474, reported to suppress seizures without considerable action. Hypothesizing that this drug could act other than R and/or a disease‐specific mechanism, we assessed effect MRS5474 on hippocampus. Experimental Approach Excitatory synaptic currents, field potentials, spontaneous activity, [ 3 H]GABA uptake GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in R) density tissue Western blot. Key Results (50–500 nM) was devoid upon excitatory signals slices, except when hyperexcitability previously induced vivo ex vivo. inhibited GABA transporter type (GAT‐1)‐mediated γ‐aminobutyric acid (GABA) uptake, action not blocked antagonist but mimicked agonist. overexpressed samples patients with epilepsy had focal resection surgery. concentration‐dependent potentiation GABA‐evoked oocytes micro‐transplanted membranes prepared epileptic non‐epileptic tissue, antagonist. Conclusion Implications We identified activates selective actions This underscores promising target for medications.

Language: Английский

Citations

2
The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors DOI Open Access

Elisabet Jakova,

Omozojie P. Aigbogun, Mohamed Taha Moutaoufik

et al.

Published: June 13, 2024

We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, hallmark of Parkinson’s disease. Here, we aimed to synthesize dimer caffeine-indan linked by 6-carbon chain cross the blood-brain barrier tested its ability bind α-synuclein, reducing misfolding, behavioural abnormalities, our rodent model. Behavioural tests histological stains assessed neuroprotective effects compound. A rapid synthesis 18F-labelled analogue enabled Positron Emission Tomography Computed imaging for biodistribution measurement. Molecular docking analysis showed binds N- C-termini non-amyloid-β-component (NAC) domain, similar 1-aminoindan, this binding promotes “loop” conformation. The also orthosteric site within receptor. Immunohistochemistry confocal abolished upregulation aggregation substantia nigra hippocampus, mitigated cognitive deficits, anxiety, despair, motor abnormalities. remained stable post-injection distributed various organs, notably brain, suggesting potential as tracer disease therapy.

Language: Английский

Citations

1
Allosteric Sites and Allosteric Regulators of G Protein-Coupled Receptors: Gray Cardinals of Signal Transduction DOI
А. О. Шпаков

Journal of Evolutionary Biochemistry and Physiology, Journal Year: 2023, Volume and Issue: 59(S1), P. S1 - S106

Published: Dec. 1, 2023

Language: Английский

Citations

2
2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives DOI Creative Commons

Filipe Areias,

Carla Correia,

Ashly Rocha

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(11), P. 2543 - 2543

Published: May 28, 2024

A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, A3 adenosine receptor subtypes. Eleven purines showed potent antagonism A3, dual A1/A2A, A1/A2B, A1/A3 receptors. Additionally, three compounds high affinity without selectivity for any specific receptor. The structure-activity relationships made this group new compounds. 9-methylpurine generally less but more selective, the 9H-purine selective. These can be an important source biochemical tools and/or pharmacological drugs.

Language: Английский

Citations

0
Selective modulation of epileptic tissue by an adenosine A3 receptor-activating drug DOI
Ana M. Sebastião, Anwesha Ghosh, Leonor Ribeiro‐Rodrigues

et al.

Authorea (Authorea), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 2, 2024

Background and Purpose Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. Development of adenosine agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R-selective agonist, MRS5474, reported to suppress seizures without considerable action. Hypothesizing that this drug could act other than A1R and/or a disease specific mechanism, we assessed effect MRS5474 on hippocampus. Experimental Approach Excitatory synaptic currents, field potentials, spontaneous activity, [3H]GABA uptake GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in A3 (A3R) density tissue Western Blot. Key Results (50-500nM) was devoid upon excitatory signals slices, except when hyperexcitability previously induced vivo ex vivo. This contrasted with agonists. inhibited GAT-1 mediated GABA uptake, action not blocked antagonist but A3R mimicked agonist. overexpressed samples patients epilepsy had focal resection surgery. concentration-dependent potentiation GABA-evoked oocytes micro-transplanted membranes prepared epileptic non-epileptic tissue, antagonist. Conclusion Implications We identified activates selective actions underscores promising target for development medications.

Language: Английский

Citations

0
The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors DOI Open Access

Elisabet Jakova,

Omozojie P. Aigbogun, Mohamed Taha Moutaoufik

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9386 - 9386

Published: Aug. 29, 2024

We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, hallmark of Parkinson’s disease. Here, we aimed to synthesize dimer caffeine-indan linked by 6-carbon chain cross the blood–brain barrier tested its ability bind α-synuclein, reducing misfolding, behavioral abnormalities, our rodent model. Behavioral tests histological stains assessed neuroprotective effects compound. A rapid synthesis 18F-labeled analogue enabled Positron Emission Tomography Computed imaging for biodistribution measurement. Molecular docking analysis showed binds N- C-termini non-amyloid-β-component (NAC) domain, similar 1-aminoindan, this binding promotes “loop” conformation. The also orthosteric site within receptor. Immunohistochemistry confocal abolished upregulation aggregation substantia nigra hippocampus, mitigated cognitive deficits, anxiety, despair, motor abnormalities. remained stable post-injection distributed various organs, notably brain, suggesting potential as tracer disease therapy.

Language: Английский

Citations

0
Problems and prospects for finding new pharmacological agents among adenosine receptor agonists, antagonists, or their allosteric modulators for the treatment of cardiovascular diseases DOI Open Access
В. Н. Перфилова, Е. А. Музыко, A. S. Taran

et al.

Biomeditsinskaya Khimiya, Journal Year: 2023, Volume and Issue: 69(6), P. 353 - 370

Published: Jan. 1, 2023

A1-adenosine receptors (A1AR) are widely distributed in the human body and mediate many different effects. They abundantly present cardiovascular system, where they control angiogenesis, vascular tone, heart rate, conduction. This makes system A1AR an attractive target for treatment of diseases (CVD). The review summarizes literature data on structure functioning A1AR, analyzes their involvement formation myocardial hypertrophy, ischemia-reperfusion damage, various types rhythm disorders, chronic failure, arterial hypertension. Special attention is paid to role some allosteric regulators as potential agents CVD treatment.

Language: Английский

Citations

1
ALLOSTERIC SITES AND ALLOSTERIC REGULATORS OF G-PROTEIN-COUPLED RECEPTORS: GRAY CARDINALS OF SIGNAL TRANSDUCTION DOI
А. О. Шпаков

Журнал эволюционной биохимии и физиологии, Journal Year: 2023, Volume and Issue: 59(7), P. 559 - 658

Published: Dec. 1, 2023

Language: Английский

Citations

1
2-Amino-5-arylethynyl-thiophen-3-yl-(phenyl)methanones as A1 Adenosine Receptor Positive Allosteric Modulators DOI
Paola Oliva,

R. Rama Suresh,

Silvia Pasquini

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(12), P. 1640 - 1646

Published: Nov. 13, 2023

A1 adenosine receptor (A1AR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure–activity relationship of 5-arylethynyl aminothiophenes as A1AR positive allosteric modulators (PAMs). The derivatives were compared in binding functional assays at human A1AR, indicating that some fluoro-substituted analogues enhanced PAM activity. identified substitution terminal phenyl ring 12 (2-F-Ph), 15 (3,4-F2-Ph, MRS7935), 21 (2-CF3-Ph) particularly enhancing was also shown to act an ago-PAM with EC50 ≈ 2 μM, without activity (30 μM) ARs. Molecular modeling indicated both 4-neopentyl groups are located a region outside transmembrane helix bundle is contact phospholipid bilayer, consistent preference for nonpolar aryl moiety. Although they hydrophobic, these PAMs could provide potential drug candidate molecules engaging protective A1ARs.

Language: Английский

Citations

0