ZM241385 IS AN ANTAGONIST OF THE FACILITATORY RESPONSES PRODUCED BY THE A(2A) ADENOSINE RECEPTOR AGONISTS CGS21680 AND HENECA IN THE RAT HIPPOCAMPUS

1 In the present study, we investigated the ability of a recently intr oduced non-xanthine A(2A) receptor antagonist, ZM241385 iazolo{2,3-a{1 ,3,5}triazin-5-yl-aminoethyl)phenol) to displace binding of the protot ypical A(2A) adenosine receptor agonist [H-3]CGS21680 ethyl)phenylamin o]-5'-N-ethylcarboxamidoadenosine) and to modify the facilitatory resp onses caused by the A(2A) selective agonists, CGS21680 and HENECA (2-h exynl-5'-N-ethylcarboxamidoadenosine) in rat hippocampal preparations. 2 ZM241385 was nearly equipotent to displace [H-3]CGS21680 (30 nM) bi nding to hippocampal (K-i of 0.52 nM) and to striatal membranes (K-i o f 0.35 nM), whereas HENECA was a more potent displacer of [H-3]CGS2168 0 binding to striatal (K-i of 4.5 nM) than to hippocampal membranes (K -i of 19 nM). 3 HENECA (3-30 nM) was equipotent with CGS21680 to facil itate veratridine-evoked [H-3]acetylcholine release from superfused hi ppocampal synaptosomes and ZM241385 (20 nM) inhibited the facilitatory effects of both HENECA (30 nM) and CGS21680 (30 nM); this antagonism was mimicked by CSC (250 nM). 4 In contrast, CGS21680 (10-30 nM) was m ore potent than HENECA (10-30 nM) to facilitate synaptic transmission in Schaffer fibres/CAl pyramid synapses of hippocampal slices and the facilitatory effect of CGS21680 (10 nM) was blocked by ZM241385 (20 nM ) whereas CSC (250 nM) caused a 40% attenuation of this CGS21680-induc ed facilitation. 5 These results indicate that ZM241385 is the first A (2A) antagonist with equal potency to displace [3H]CGS21680 binding to striatal and limbic regions, and with general efficiency to antagoniz e HENECA- or CGS21680-mediated facilitatory responses in the hippocamp us.