Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Abstract

1 We have characterized the in vitro pharmacological profile of putative A2 adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[l ,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 (Ki = 0.074 nM) and selective (28 fold) drug on A2 receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. The data provided a basis to reduce, by further chemical modifications, the affinity at Al receptor and therefore enhance A2 receptor selectivity.

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A2a selective adenosine receptor antagonist

“…In addition to its limited selectivity in functional studies, the lack of information of activity of 8-(3-chlorostyryl)-1,3-dipropyl-xanthine at A2b receptor subtypes (Jacobson et al, 1993) A2a selectivity in functional assays (Dionisotti et al, 1994). ZM 241385 had 30-80 fold selectivity for A2a over A2b receptors.…”

“…CGS 1 5943 (5-amino-9-chloro-2 -(2-furyl)-pyrazolo-[4,3 -e]1,2,4 -triazolo [1,5-c]quinazoline) has high affinity for the A2a receptor (Ki 3 nM) but modest A2a: Al selectivity (7 fold) (Williams et al, 1987). Dionisotti et al (1994) (Williams et al, 1986), rat cloned A3 receptors expressed in chinese hamster ovary cell line (Olah et al, 1994) and in rat cortex (Bruns et al, 1987a) respectively. Evaluation of antagonism of adenosine receptor-mediated responses was further investigated in guinea-pig atria (Al receptor, Collis, 1983), guinea-pig Langendorff hearts (A2a receptor, Ueeda et al, 1991) and guinea-pig isolated aortae (A2b receptor, Hargreaves et al, 1991;Martin, 1992).…”

Brief Antecedent Ischemia Enhances Recombinant Tissue Plasminogen Activator–Induced Coronary Thrombolysis by Adenosine-Mediated Mechanism

“…1,2 As a result, we propose that the absence of protection seen in PC dogs treated with CGS is a consequence of poor patency (prolonged duration of ischemia) that is due to the inhibition of platelet A 2 receptors. However, this conclusion is confounded by the fact that PC-induced cardioprotection is initiated by stimulation of adenosine A 1 /A 3 receptors on myocyte membranes, 2 and CGS, despite its nanomolar affinity for the A 2 receptor, is not subtype specific 12,13 ; ie, the loss of protection seen in PC dogs that received CGS could be due in part to residual A 1 receptor antagonism on myocytes.…”

“…We observed no deleterious changes in patency, consistent with ex vivo evidence showing CGS to be devoid of intrinsic effects on platelet aggregation. 12,13 An explanation for the poor patency in CGS-treated dogs may be derived from evidence from a canine model of hypoperfusion, which showed that maintenance of stable coronary blood flow is dependent on endogenous adenosine; ie, infusion of a nonselective adenosine receptor antagonist initiated a progressive deterioration in coronary perfusion that was due to the formation of platelet thrombi. 7,8 Thus, even in non-PC controls, adenosine may participate in the regulation of platelet activity and coronary patency.…”

“…In this case, however, all animals received the adenosine A 2 /A 1 receptor antagonist CGS 15943 4,12,13 (CGS, 1.5 mg/kg IV bolus, a gift from Novartis Inc, Summit, New Jersey) 10 minutes before the PC (nϭ6) or control period (nϭ7, Figure 1). Time to lysis, LAD patency during the 2 hours after lysis, and infarct size were quantified as in protocol 2.…”