Among the heterocyclic structures identified as potent human A3 (hA3) adenosine receptor's antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C2-furyl ring, not only confer a good pharmacol. profile (with significantly enhanced selectivity against other adenosine receptor subtypes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA3 receptor in the low nanomolar range. The most potent deriv. of the series presented better affinity and excellent selectivity (compd. 31, Ki hA3 = 0.108 nM; hA1/hA3 = 5200; hA2A/hA3 = 7200), in comparison to the C2-furyl counterpart. A receptor-driven mol. modeling investigation, based on a recently proposed model of A3 receptor derived from the crystallog. structure of human A2A receptor, has been carried out in order to support the exptl. binding data and to justify the enhanced selectivity against the other receptor subtypes.
The Significance of 2-Furyl Ring Substitution with a 2-(para-substituted) Aryl Group in a New Series of Pyrazolo-triazolo-pyrimidines as Potent and Highly Selective hA3 Adenosine Receptors Antagonists: New Insights into Structure-Affinity Relationship and Receptor-Antagonist Recognition
CACCIARI, Barbara;
2010
Abstract
Among the heterocyclic structures identified as potent human A3 (hA3) adenosine receptor's antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C2-furyl ring, not only confer a good pharmacol. profile (with significantly enhanced selectivity against other adenosine receptor subtypes) but also overcome the metabolic transformation of the furan ring into toxic intermediates. All the synthesized [2-(para-substituted) phenyl]-pyrazolo-triazolo-pyrimidines showed affinity at the hA3 receptor in the low nanomolar range. The most potent deriv. of the series presented better affinity and excellent selectivity (compd. 31, Ki hA3 = 0.108 nM; hA1/hA3 = 5200; hA2A/hA3 = 7200), in comparison to the C2-furyl counterpart. A receptor-driven mol. modeling investigation, based on a recently proposed model of A3 receptor derived from the crystallog. structure of human A2A receptor, has been carried out in order to support the exptl. binding data and to justify the enhanced selectivity against the other receptor subtypes.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
