Gigliola Sulis speaks to Ann Goldstein: writing locally, translating globally

The conversation focuses on attitudes and trends in the US publishing market toward translated fiction. The strategies used by Goldstein as a translator of geo-centred and multilingual Italian novels are analysed, with reference to her translations of Pier Paolo Pasolini, Primo Levi, Elena Ferrante, Milena Agus, and Amara Lakhous

Comparison of CGS 15943, ZM 241385 and SCH 58261 as antagonists at human adenosine receptors

Three structurally related non-xanthine compounds, CGS 15943, ZM 241385 and SCH 58261, are potent A2A adenosine receptor antagonists and have been used as tools in many pharmacological studies. We have now characterized their affinity and selectivity profile on human adenosine receptors stably transfected into either CHO cells (A1 and A2B receptors) or HEK-293 cells (A2A and A3 receptors). In binding studies using [3H]SCH 58261 as a radioligand, the three compounds were equally potent at A2A receptors, their K(i) value being less than 1 nM. Affinity for A1 and A3 receptors was measured using [3H]DPCPX and [125I]AB-MECA as radioligands. Given the lack of selective ligands, interaction with A2B receptors was assessed using the cAMP accumulation assay following stimulation by the adenosine receptor agonist N-ethylcarboxamidoadenosine (NECA). CGS 15943 was almost as potent at A1 receptors (K(i)3.5 nM) as at A2A receptors, showed moderate affinity for A3 receptors (K(i) 95 nM) and also interacted with A2B receptors (K(i) 44 nM; pA2 7.5). ZM 241385 showed little affinity for A1 receptors (K(i) 255 nM), and did not interact with A3 receptors (K(i)>10 microM); however, it displayed moderate affinity for A2B receptors (K(i) 50 nM; pA2 7.3). SCH 58261 had weak affinity for A1 receptors (K(i) 287 nM), no interaction with A3 receptors (K(i)>10 microM), and showed negligible interaction with A2B receptors (K(i) 5 microM; pA2 6.0). These data indicate that SCH 58261 is the most selective A2A antagonist currently available. Moreover, the different receptor selectivity of these three chemically related compounds provides useful information to progress with structure-activity relationship studies

Effects of adenosine derivatives on human and rabbit platelet aggregation. Correlation of adenosine receptor affinities and antiaggregatory activity

The inhibitory effects of several adenosine analogues, including the new A2-selective agonists 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680) and 2-hexynyl-5'-N-ethylcarbox-amidoadenosine (2-hexynyl-NECA), were investigated in vitro on human and rabbit platelet aggregation. The compounds examined inhibited ADP-induced platelet aggregation over a wide range of potency. The rank order of activity was similar between the two species thus showing that the rabbit is a useful animal model for studying the effects of adenosine derivatives on platelet aggregation. 2-Hexynyl-NECA was found to be the most potent adenosine compound of those currently available, having IC50 values of 0.10 and 0.07 microM in human and rabbit platelets, respectively. Conversely, the A1 agonists R(-)-N6-(2-phenylisopropyl) adenosine (R-PIA), S(+)-N6-(2-phenylisopropyl) adenosine (S-PIA) and 2-chloro-N6-cyclopentyladenosine (CCPA) were the least potent compounds with IC50 values in the micromolar range. The potency of the compounds in inhibiting platelet aggregation was found to be highly correlated with their affinity for A2 receptors as measured using 3H-CGS 21680 binding in rat brain striatum

Neuropharmacology of the adenosine A2a receptors

Studies done over the last 20 years have clearly shown that the adenosine A2A receptors are abundant in the striatum of several animal species. A2A receptors have also been found in the cerebral cortex and hippocampus. The distribution of A2A receptors closely matches that of dopamine D2 receptors, being expressed in striatopallidal GABAergic neurons that also express enkephalin. A variety of functional and behavioural studies have shown that antagonistic interactions exist between the A2A and D2 receptors. Thus, blockade of A2A receptors mimics the action of dopamine D2 receptor agonists. More recent studies have indicated that A2A receptors interact more broadly with dopaminergic pathways, D1 receptors are also involved in such interactions. Altogether, a variety of data support the suggestion that A2A receptor antagonists have a potential for treatment of Parkinson's disease, whereas A2A receptor agonists, which inhibit motor behaviour, may possess neuroleptic properties. Great progress is being made thanks to the development of potent and selective A2A receptor antagonists, notably the xanthines KF 17837 and CSC, and the non-xanthine heterocycle SCH 58261. These compounds and their radiolabelled forms make it possible to elucidate the role of brain A2A receptors further and open the way to the development of new agents for treatment of central nervous system disorder