scholarly journals P109Opposite actions of atrial adenosine A1 receptor on G protein-coupled inwardly-rectifying potassium (GIRK/Kir3.1/3.4) and small Ca2+-activated K+ outward (KCa2/SK) currents

2014 ◽  
Vol 103 (suppl 1) ◽  
pp. S18.5-S19
Author(s):  
B Braganca ◽  
N Oliveira-Monteiro ◽  
S Nogueira-Marques ◽  
F Ferreirinha ◽  
PA Lima ◽  
...  
Keyword(s):  
G Protein ◽  
Adenosine A1 Receptor ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Inwardly Rectifying ◽  
G Protein Coupled

scholarly journals The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

2020 ◽  
Vol 22 (1) ◽  
pp. 320
Author(s):  
Jeroen Spanoghe ◽  
Lars E. Larsen ◽  
Erine Craey ◽  
Simona Manzella ◽  
Annelies Van Dycke ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Neuronal Inhibition ◽  
Adenosine A1 ◽  
Mitogen Activated Protein ◽  
A1 Receptor ◽  
G Protein Coupled

Adenosine acts as an endogenous anticonvulsant and seizure terminator in the brain. Many of its anticonvulsive effects are mediated through the activation of the adenosine A1 receptor, a G protein-coupled receptor with a wide array of targets. Activating A1 receptors is an effective approach to suppress seizures. This review gives an overview of the neuronal targets of the adenosine A1 receptor focusing in particular on signaling pathways resulting in neuronal inhibition. These include direct interactions of G protein subunits, the adenyl cyclase pathway and the phospholipase C pathway, which all mediate neuronal hyperpolarization and suppression of synaptic transmission. Additionally, the contribution of the guanyl cyclase and mitogen-activated protein kinase cascades to the seizure-suppressing effects of A1 receptor activation are discussed. This review ends with the cautionary note that chronic activation of the A1 receptor might have detrimental effects, which will need to be avoided when pursuing A1 receptor-based epilepsy therapies.

scholarly journals Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Kerry Barkan ◽  
Barbara Preti ◽  
Michele Leuenberger ◽  
Mark Wall ◽  
...  
Keyword(s):  
Drug Design ◽  
Binding Mode ◽  
Adenosine A1 Receptor ◽  
Dissociation Pathway ◽  
Binding Mechanism ◽  
Structure Based Drug Design ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Dynamics Simulations ◽  
G Protein Coupled

ABSTRACTDespite being amongst the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and highlight the dramatic effect that chemical modifications can have on the overall binding mechanism.

Adenosine A1 receptor-dependent G-protein activity in the rat brain during prolonged wakefulness

Neuroreport ◽  
2004 ◽  
Vol 15 (13) ◽  
pp. 2133-2137 ◽  
Author(s):  
Lauri O. Alanko ◽  
Jarmo T. Laitinen ◽  
Dag Stenberg ◽  
Tarja Porkka-Heiskanen
Keyword(s):  
Rat Brain ◽  
G Protein ◽  
Adenosine A1 Receptor ◽  
Protein Activity ◽  
Adenosine A1 ◽  
A1 Receptor

scholarly journals Design, Synthesis and Pharmacological Profile of LUF7746, a Novel Covalent Partial Agonist for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Xue Yang ◽  
Majlen Dilweg ◽  
Dion Osemwengie ◽  
Lindsey Burggraaff ◽  
Daan van der Es ◽  
...  
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Activation Process ◽  
Full Agonist ◽  
Partial Agonists ◽  
Activation Assay ◽  
Adenosine A1 ◽  
A1 Receptor

Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.<br>

scholarly journals Design, Synthesis and Pharmacological Profile of LUF7746, a Novel Covalent Partial Agonist for the Adenosine A1 Receptor

2020 ◽  
Author(s):  
Xue Yang ◽  
Majlen Dilweg ◽  
Dion Osemwengie ◽  
Lindsey Burggraaff ◽  
Daan van der Es ◽  
...  
Keyword(s):  
G Protein ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Adenosine A1 Receptor ◽  
Activation Process ◽  
Full Agonist ◽  
Partial Agonists ◽  
Activation Assay ◽  
Adenosine A1 ◽  
A1 Receptor

Partial agonists for G protein-coupled receptors (GPCRs) provide opportunities for novel pharmacotherapies with enhanced on-target safety compared to full agonists. For the human adenosine A1 receptor (hA1AR) this has led to the discovery of capadenoson, which has been in phase IIa clinical trials for heart failure. Accordingly, the design and profiling of novel hA1AR partial agonists has become an important research focus. In this study, we report on LUF7746, a capadenoson derivative bearing an electrophilic fluorosulfonyl moiety, as an irreversibly binding hA1AR modulator. Meanwhile, a nonreactive ligand bearing a methylsulfonyl moiety, LUF7747, was designed as a control probe in our study. In a radioligand binding assay, LUF7746’s apparent affinity increased to nanomolar range with longer pre-incubation time, suggesting an increasing level of covalent binding over time. Moreover, compared to the reference full agonist CPA, LUF7746 was a partial agonist in a hA1AR-mediated G protein activation assay and resistant to blockade with an antagonist/inverse agonist. An in silico structure-based docking study combined with site-directed mutagenesis of the hA1AR demonstrated that amino acid Y2717.36 was the primary anchor point for the covalent interaction. Additionally, a label-free whole-cell assay was set up to identify LUF7746’s irreversible activation of an A1 receptor-mediated cell morphological response. These results led us to conclude that LUF7746 is a novel covalent hA1AR partial agonist and a valuable chemical probe for further mapping the receptor activation process. It may also serve as a prototype for a therapeutic approach in which a covalent partial agonist may cause less on-target side effects, conferring enhanced safety compared to a full agonist.<br>

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