EFFECTS OF THE NEW A(2) ADENOSINE RECEPTOR ANTAGONIST 8FB-PTP, AN 8 SUBSTITUTED PYRAZOLO-TRIAZOLO-PYRIMIDINE, ON IN-VITRO FUNCTIONAL MODELS

1 We have characterized the in vitro pharmacological profile of putative A(2) adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (8FB-PTP) and 5-amino-9-chloro-2-(2-furyl 1,2,4-triazolo [1,5-c] quinazoline (CGS 15943), and the xanthine derivative (E)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropyl-xanthine (KF 17837). 2 In binding studies on bovine brain, 8FB-PTP was the most potent (K-i = 0.074 nM) and selective (28 fold) drug on A(2) receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. 3 In functional studies, 8FB-PTP antagonized 5'-N-ethyl-carboxamidoadeno sine (NECA)-induced vasorelaxation of bovine coronary artery (pA(2) = 7.98) and NECA-induced inhibition of rabbit platelet aggregation (pA(2)=8.20). CGS 15943 showed weak activity in the platelet aggregation model (pA(2) = 7.43) and failed to antagonize NECA-induced vasodilatation. KF 17837 was ineffective in both models up to micromolar concentrations. 4 Antagonism of A(1)-mediated responses was tested versus 2-chloro-N-6-cyclopentyladenosine (CCPA) in rat atria. 8FB-PTP and CGS 15943 also antagonized competitively the negative chronotropic response induced by CCPA. Conversely, KF 17837 was unable to reverse A(1)-mediated responses. 5 8FB-PTP is a potent and competitive antagonist of responses mediated by A(2) adenosine receptors. The data provided a basis to reduce, by further chemical modifications, the affinity at A(1) receptor and therefore enhance A(2) receptor selectivity.