A number of 1,3-dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines were prepared and evaluated as ligands of recombinant human adenosine receptors (hARs). Several 1,3-dipropyl derivatives endowed with nanomolar binding affinity at hA2B receptors, but poor selectivity over hA2A, hA1 and hA3 AR subtypes were identified. A comparison with the corresponding 7-OH- and 7,9-unsubstituted-deazaxanthines revealed that 9-OH-9-deazaxanthines are more potent hA2B ligands with lower partition coefficients and higher water solubility compared to the other two congeneric classes of deazaxanthines. An optimization of the para-substituent of the 8-phenyl ring of 9-OH-9-deazaxanthines led to the discovery of compound 38, which exhibited outstanding hA2B affinity (Ki = 1.0 nM), good selectivity over hA2A, hA1 and hA3 (selectivity indices = 100, 79 and 1290, respectively) and excellent antagonist potency in a functional assay on rat A2B (pA2B = 9.33).

1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines as potent A2B adenosine receptor antagonists: design, synthesis, structure-affinity and structure-selectivity relationships

STEFANACHI, ANGELA;NICOLOTTI, ORAZIO;LEONETTI, Francesco;CELLAMARE, Saverio;CAMPAGNA, Francesco;CAROTTI, Angelo
2008

Abstract

A number of 1,3-dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines were prepared and evaluated as ligands of recombinant human adenosine receptors (hARs). Several 1,3-dipropyl derivatives endowed with nanomolar binding affinity at hA2B receptors, but poor selectivity over hA2A, hA1 and hA3 AR subtypes were identified. A comparison with the corresponding 7-OH- and 7,9-unsubstituted-deazaxanthines revealed that 9-OH-9-deazaxanthines are more potent hA2B ligands with lower partition coefficients and higher water solubility compared to the other two congeneric classes of deazaxanthines. An optimization of the para-substituent of the 8-phenyl ring of 9-OH-9-deazaxanthines led to the discovery of compound 38, which exhibited outstanding hA2B affinity (Ki = 1.0 nM), good selectivity over hA2A, hA1 and hA3 (selectivity indices = 100, 79 and 1290, respectively) and excellent antagonist potency in a functional assay on rat A2B (pA2B = 9.33).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/124430
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