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J Med Chem. 2009 Apr 9;52(7):2098-108. doi: 10.1021/jm801659w.

Novel 2- and 4-substituted 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the A3 adenosine receptor.

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Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA


4-Arylamino and 2- cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A(3) adenosine receptor (AR). In addition to allosteric modulation of the maximum functional efficacy (in [(35)S]GTPgammaS G protein binding assay) of the A(3)AR agonist Cl-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at the 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A(3)AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A(3)AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A(3)AR activity and improved selectivity in comparison to inhibition of orthosteric binding.

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