ZM241385 is an antagonist of the facilitatory responses produced by the A_2A adenosine receptor agonists CGS21680 and HENECA in the rat hippocampus

Abstract

1. In the present study, we investigated the ability of a recently introduced non-xanthine A_2A receptor antagonist, ZM241385 (4-(2-[7-amino-2-(2-furyl{1,2,4}-triazolo{2,3-a{1,3,5}triazin-5-yl-aminoethyl)phenol) to displace binding of the prototypical A_2A adenosine receptor agonist [³H]CGS21680 (2-[4-(2-p-carboxyethyl)phenylamino]-5′-N-ethylcarboxamidoadenosine) and to modify the facilitatory responses caused by the A_2A selective agonists, CGS21680 and HENECA (2-hexynl-5′-N-ethylcarboxamidoadenosine) in rat hippocampal preparations.

2. ZM241385 was nearly equipotent to displace [³H]CGS21680 (30 nM) binding to hippocampal (K_i of 0.52 nM) and to striatal membranes (K_i of 0.35 nM), whereas HENECA was a more potent displacer of [³H]CGS21680 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 facilitate veratridine-evoked [³H]acetylcholine release from superfused hippocampal 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 more potent than HENECA (10–30 nM) to facilitate synaptic transmission in Schaffer fibres/CA1 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-induced 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 antagonize HENECA- or CGS21680-mediated facilitatory responses in the hippocampus.

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