N6-1,3-Diphenylurea derivatives of 2-phenyl-9-benzyladenines and 8-azaadenines: Synthesis and biological evaluation as allosteric modulators of A2A adenosine receptors

Giorgi, Irene; Biagi, Giuliana; Bianucci, Anna Maria Paola; Borghini, Alice; Livi, Oreste; Leonardi, Michele; Pietra, Daniele; Calderone, Vincenzo; Martelli, Alma

doi:10.1016/j.ejmech.2007.10.021

Cited by 25 publications

(24 citation statements)

References 13 publications

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“…In addition, the inability of 3,7-dimethyl-1-propargylxanthine, a blocker of adenosine A 2 receptors, to reverse the NS1643-induced increase of I K(Ca) in GH 3 cells was found in our study (data not shown). Therefore, its stimulatory action on I K(Ca) seen in these cells is unlikely to be mediated by the binding to adenosine receptors (Giorgi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Potent Activation of Large-Conductance Ca2+-Activated K+ Channels by the Diphenylurea 1,3-Bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643) in Pituitary Tumor (GH3) Cells

Peng²,

Chen³

et al. 2008

Molecular Pharmacology

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1,3-Bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643) isreported to be an activator of human ether-à -go-go-related gene current. However, it remains unknown whether it has any effects on other types of ion channels. The effects of NS1643 on ion currents and membrane potential were investigated in this study. NS1643 stimulated Ca 2ϩ -activated K ϩ current [I K(Ca) ] in a concentration-dependent manner with an EC 50 value of 1.8 M in pituitary tumor (GH 3 ) cells. In inside-out recordings, this compound applied to the intracellular side of the detached channels stimulated large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels with no change in single-channel conductance. It shifted the activation curve of BK Ca channels to less depolarized voltages without altering the gating charge of the channels. NS1643-stimulated channel activity depended on intracellular Ca 2ϩ , and mean closed time during exposure to NS1643 was reduced. NS1643 (3 M) had little or no effect on peak amplitude of ether-à -go-go-related gene-mediated K ϩ current evoked by membrane hyperpolarization, although it increased the amplitude of late-sustained components of K ϩ inward current, which was suppressed by paxilline but not by azimilide. NS1643 (3 M) had no effect on L-type Ca 2ϩ current. This compound reduced repetitive firing of action potentials, and further application of paxilline attenuated its decrease in firing rate. In addition, NS1643 enhanced BK Ca -channel activity in human embryonic kidney 293T cells expressing ␣-hSlo. In summary, we clearly show that NS1643 interacts directly with the BK Ca channel to increase the amplitude of I K(Ca) in pituitary tumor (GH 3 ) cells. The ␣-subunit of the channel may be a target for the action of this small compound. NS1643 (Fig.

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Section: Discussionmentioning

confidence: 99%

Potent Activation of Large-Conductance Ca2+-Activated K+ Channels by the Diphenylurea 1,3-Bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643) in Pituitary Tumor (GH3) Cells

Peng²,

Chen³

et al. 2008

Molecular Pharmacology

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“…A 2-phenyl-9-benzyl-8-azaadenine derivative (Fig. 10) was reported to be an allosteric enhancer of radioligand binding at the A 2A adenosine receptor and agonist-induced relaxation of rat aortic rings (Giorgi et al, 2008). The benzopyran-2-one derivative 4-methyl-2-oxo-2H-chromen-7-yl methylcarbamate (PD120,918) was also reported to be an enhancer of binding at the A 2A receptor (Gao et al, 2005).…”

Section: A 2a Receptor Allosteric Modulatorsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

Fredholm¹,

IJzerman²,

Jacobson³

et al. 2011

Pharmacol Rev

1,936

2,797

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“…In a study of a chemical series of adenine and 8‐azaadenine derivatives, A 1 R PAM compound 7 was selective for A 1 R, while 8 was identified as a PAM with improved selectivity for A 2A R . Compound 8 was found to act as a PAM in A 2A R in equilibrium displacement studies using both radioligand [ 3 H]ZM241385 and [ 3 H]CGS21680.…”

Section: Resultsmentioning

confidence: 99%

“…Starting with our models for A 1 R, as the radioligand [ 3 H]CCPA was utilized in experimental studies of the bitopic ligands and to characterize PAM activity for all of our model A 1 R PAMs ( 1–5 ), it was selected as the common bound agonist in our A 1 R models Figure a. For our studies of the A 2A R selective PAM 8 , docking was performed using the thermostabilized A 2A R crystal structure bound with the selective agonist CGS21680 (4UG2.pdb), which was utilized in the experimental characterization of 8 …”

Section: Methodsmentioning

confidence: 99%

Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors

2017

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Following insights from recent crystal structures of the muscarinic acetylcholine receptor, binding modes of Positive Allosteric Modulators (PAMs) were predicted under the assumption that PAMs should bind to the extracellular surface of the active state. A series of well-characterized PAMs for adenosine (A1R, A2AR, A3R) and muscarinic acetylcholine (M1R, M5R) receptors were modeled using both rigid and flexible receptor CHARMM-based molecular docking. Studies of adenosine receptors investigated the molecular basis of the probe-dependence of PAM activity by modeling in complex with specific agonist radioligands. Consensus binding modes map common pharmacophore features of several chemical series to specific binding interactions. These models provide a rationalization of how PAM binding slows agonist radioligand dissociation kinetics. M1R PAMs were predicted to bind in the analogous M2R PAM LY2119620 binding site. The M5R NAM (ML-375) was predicted to bind in the PAM (ML-380) binding site with a unique induced-fit receptor conformation.

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N6-1,3-Diphenylurea derivatives of 2-phenyl-9-benzyladenines and 8-azaadenines: Synthesis and biological evaluation as allosteric modulators of A2A adenosine receptors

Cited by 25 publications

References 13 publications

Potent Activation of Large-Conductance Ca2+-Activated K+ Channels by the Diphenylurea 1,3-Bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643) in Pituitary Tumor (GH3) Cells

Potent Activation of Large-Conductance Ca2+-Activated K+ Channels by the Diphenylurea 1,3-Bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643) in Pituitary Tumor (GH3) Cells

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors

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