title: ZM241385 is an antagonist of the facilitatory responses produced by the A2A 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 A2A 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 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-ethylcarboxamidoadenosine) 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]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 A2A 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.
authors.affiliation: Department of Chemistry & Biochemistry, Faculty of Sciences, University of Lisbon, Campo Grande, Portugal.
authors.forename: R A
authors.initials: RA
authors.lastname: Cunha
authors.forename: M D
authors.initials: MD
authors.lastname: Constantino
authors.forename: J A
authors.initials: JA
authors.lastname: Ribeiro
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D006624:Hippocampus / Q000187:drug effects*; D008024:Ligands; D008566:Membranes / Q000187:drug effects; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014793:Visual Cortex / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D008024:Ligands; D010627:Phenethylamines; D010975:Platelet Aggregation Inhibitors; D058906:Purinergic P1 Receptor Agonists; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C076864:2-hexynyladenosine-5'-N-ethylcarboxamide; D019830:Adenosine-5'-(N-ethylcarboxamide); D000241:Adenosine; D000109:Acetylcholine