- Novel adenosine A2A receptor ligands: A synthetic, functional and computational investigation of selected literature adenosine A2A receptor antagonists for extending into extracellular space
-
Growing evidence has suggested a role in targeting the adenosine A 2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position.
- J?rg, Manuela,Shonberg, Jeremy,Mak, Frankie S.,Miller, Neil D.,Yuriev, Elizabeth,Scammells, Peter J.,Capuano, Ben
-
p. 3427 - 3433
(2013/06/26)
-
- Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds
-
Cyclin-dependent kinases (cdk) have recently raised considerable interest in view of their essential role in the regulation of the cell division cycle. The structure-activity relationships of edk inhibition showed that the 1, 3, and 7 positions of the purine ring must remain free, probably for a direct interaction, in which it behaves as a hydrogen bond acceptor. Olomoucine (6-(benzylamino)-2-[(2-hydroxyethyl)amino]-9-methylpurine, OC), roscovitine (6-(benzylamino)2(R)-[[1-(hydroxymethyl)propyl]amino]-9- isopropylpurine), and other N6,2,9-trisubstituted adenines were found to exert a strong inhibitory effect on the p34(cdc2)/cyclin B kinase. Removal or change of the side chain at position 2 or the hydrophobic group at position 9 dramatically decreased the inhibitory activity of olomoucine or roscovitine. Inhibition of cdk with OC and related compounds clearly arrests cell proliferation of many tumor cell lines at G1/S and G2/M transitions and also triggers apoptosis in the target tumor cells in vitro and in vivo. Thus, from a pharmacological point of view, OC may represent a model compound for a new class of antimitotic and antitumor drugs.
- Havlí?ek, Libor,Hanu?, Jan,Vesely, Jaroslav,Leclerc, Sophie,Meijer, Laurent,Shaw, Gordon,Strnad, Miroslav
-
p. 408 - 412
(2007/10/03)
-
- N6,9-Disubstituted Adenines: Potent, Selective Antagonists at the A1 Adenosine Receptor
-
N6-Substituted 9-methyladenines are potent antagonists of the activation of A1 adenosine receptors.The present study assessed the effect of N6 and N-9-substituents on the binding of adenines to the A1 and A2 receptors, respectively, of rat brain cortex and striatum and also on the antagonism of the A2 receptor mediated stimulation of the adenylate cyclase of PC12 cells by N-ethyladenosine-5'-uronamide.The potency ranking of 9-substituted adenines varied directly with the hydrophobicity of the substituent: cyclopentyl > phenyl > tetrahydrofuryl > ethyl > methyl > 2-hydroxyethyl.The 9-substituted adenines showed little selectivity for either receptor and the R enantiomer of N6-(1-phenyl-2-propyl)-9-methyladenine was only 4-fold more potent than the S enantiomer at the A1 receptor.An N6-cyclopentyl substituent increased potency at the A1 receptor and decreased potency at the A2 receptor, resulting in selectivity for the A1 receptor of up to 39-fold.The N6-cyclopentyl group completely overshadowed the effect of the hydrophobicity of the 9-substituent.A 2-chloro substituent did not alter the potency of an N6-substituted 9-methyladenine.
- Thompson, Robert D.,Secunda, Sherrie,Daly, John W.,Olsson, Ray A.
-
p. 2877 - 2882
(2007/10/02)
-