ZM241385 is an antagonist of the facilitatory responses produced by the A2A adenosine receptor agonists CGS21680 and HENECA in the rat hippocampus

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Abstract
Nol) to displace binding of the prototypical A2A adenosine receptor agonist (3H)CGS21680 (2-(4-(2-p- carboxyethyl)phenylamino)-5'-N-ethylcarboxamidoadenosine) and to modify the facilitatory responses caused by the A2A selective agonists, CGS21680 and HENECA (2-hexynl-5'-N-ethylcarboxamidoadeno- sine) in rat hippocampal preparations. 2 ZM241385 was nearly equipotent to displace (3H)CGS21680 (30 nM) binding to hippocampal (Ki of 0.52 nM) and to striatal membranes (Ki of 0.35 nM), whereas HENECA was a more potent displacer of (3H)CGS21680 binding to striatal (Ki of 4.5 nM) than to hippocampal membranes (Ki of 19 nM). 3 HENECA (3-30 nM) was equipotent with CGS21680 to facilitate veratridine-evoked (3H)acetylcho- line release from superfused hippocampal synaptosomes and ZM241385 (20 nM) inhibited the facilitatory eÄects 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 SchaÄer fibres/CA1 pyramid synapses of hippocampal slices and the facilitatory eÄect 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 A2A antagonist with equal potency to displace (3H)CGS21680 binding to striatal and limbic regions, and with general eÅciency to antagonize HENECA- or CGS21680-mediated facilitatory responses in the hippocampus.

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