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

Abstract

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. 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). 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). 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. 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.

Transducing system operated by adenosine A2A receptors to facilitate acetylcholine release in the rat hippocampus

“…1A), as previously described (Cunha et al, 1995(Cunha et al, , 1997. The concentration-dependent curve for the facilitation of the evoked release of acetylcholine was similar for the two agonists, with increasing effects with increasing applied concentrations of the agonist, CGS 21680 being slightly more potent than HENECA (Fig.…”

“…Previous studies by our group had already tentatively characterized this facilitatory effect of acetylcholine release by CGS 21680 and HENECA as being mediated by adenosine A 2A receptors based on the efficiency of the adenosine A 2A receptor antagonists, CSC (8-(3-chlorostyryl)caffeine) and of ZM 241385, to prevent these effects (Cunha et al, 1995(Cunha et al, , 1997. However, some studies have cast doubts on the real selectivity of CSC and of ZM 241385 (Cunha et al, 1996;de Mendonc ßa and Ribeiro, 1994;Lindström et al, 1996;Lopes et al, 1999a) towards adenosine A 1 receptormediated responses.…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…Thus, in these hippocampal excitatory nerve terminals, there are two mechanisms responsible for the formation of extracellular adenosine and two adenosine receptors (A 1 Rs and A 2A Rs) with opposite effects on glutamate release. And electrophysiological studies at these synapses revealed that the inhibitory effects of A 1 Rs clearly predominate at low frequencies of nerve stimulation, since blockade of A 2A Rs, but not A 1 Rs, is devoid of effects [31,115]. However, stimulation with burst of high frequencies reveals a tonic activation of A 2A Rs [116] and inhibition of ecto-5 0 -nucleotidase blunts the tonic activation of A 2A Rs [113,117].…”

Potential Therapeutic Interest of Adenosine A2A Receptors in Psychiatric Disorders

“…These A 2A receptors control both the release of glutamate [35,42,43] as well as NMDA receptors [44]. Interestingly, these receptors do not seem to be activated by ambient levels of adenosine [44][45][46]. Instead, they are selectively recruited upon high frequency trains of afferent stimulation that are normally used to trigger synaptic plasticity phenomena [44].…”