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Among the heterocyclic structures identified as potent human A(3) (hA(3)) adenosine receptor's antagonists, we have demonstrated that the new pyrazolo-triazolo-pyrimidines, bearing an aryl group in replacement of the C(2)-furyl ring, not only confer a good pharmacological profile (with significantly enhanced selectivity against other adenosine receptor subytpes) 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 hA(3) receptor in the low nanomolar range. The most potent derivative of the series presented better affinity and excellent selectivity (compound 31, K(i) hA(3) = 0.108 nM; hA(1)/hA(3) = 5200; hA(2A)/hA(3) = 7200), in comparison to the C(2)-furyl counterpart. A receptor-driven molecular modeling investigation, based on a recently proposed model of A(3) receptor derived from the crystallographic structure of human A(2A) receptor, has been carried out in order to support the experimental binding data and to justify the enhanced selectivity against the other receptor subtypes.

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To further investigate new potent and selective human A(1) adenosine receptor agonists, we have synthesized a series of 5'-chloro-5'-deoxy- and 5'-(2-fluorophenylthio)-5'-deoxy-N(6)-cycloalkyl(bicycloalkyl)-substituted adenosine and 2'-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A(1), A(2A), A(2B), and A(3) adenosine receptors. In the series of N(6)-cyclopentyl- and N(6)-(endo-norborn-2-yl)adenosine derivatives, 5'-chloro-5'-deoxy-CPA (1) and 5'-chloro-5'-deoxy-(+/-)-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA(1) vs the other human receptor subtypes. The higher affinity and selectivity of 5'-chloro-5'-deoxyribonucleoside derivatives 1 and 3 for hA(1) AR vs hA(3) AR compared to that of the parent 5'-hydroxy compounds CPA and (+/-)-ENBA was rationalized by a molecular modeling analysis. 5'-Chloro-5'-deoxy-(+/-)-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p.