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Flow Synthesis and Biological Studies of an Analgesic Adamantane Derivative That Inhibits P2X7-Evoked Glutamate Release.

ABSTRACT: We report the biological evaluation of a class of adamantane derivatives, which were achieved via modified telescoped machine-assisted flow procedure. Among the series of compounds tested in this work, 5 demonstrated outstanding analgesic properties. This compound showed that its action was not mediated through direct interaction with opioid and/or cannabinoid receptors. Moreover, it did not display any significant anti-inflammatory properties. Experiments carried out on rat cerebrocortical purified synaptosomes indicated that 5 inhibits the P2X7-evoked glutamate release, which may contribute to its antinociceptive properties. Nevertheless, further experiments are ongoing to characterize the pharmacological properties and mechanism of action of this molecule.

SUBMITTER: Battilocchio C

PROVIDER: S-EPMC4027228 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Flow Synthesis and Biological Studies of an Analgesic Adamantane Derivative That Inhibits P2X7-Evoked Glutamate Release.

Battilocchio Claudio C Guetzoyan Lucie L Cervetto Chiara C Di Cesare Mannelli Lorenzo L Frattaroli Daniela D Baxendale Ian R IR Maura Guido G Rossi Antonietta A Sautebin Lidia L Biava Mariangela M Ghelardini Carla C Marcoli Manuela M Ley Steven V SV

ACS medicinal chemistry letters 20130522 8

We report the biological evaluation of a class of adamantane derivatives, which were achieved via modified telescoped machine-assisted flow procedure. Among the series of compounds tested in this work, 5 demonstrated outstanding analgesic properties. This compound showed that its action was not mediated through direct interaction with opioid and/or cannabinoid receptors. Moreover, it did not display any significant anti-inflammatory properties. Experiments carried out on rat cerebrocortical puri ...[more]

PMID: 24900736

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Project description:BackgroundBehavioral stress is recognized as a main risk factor for neuropsychiatric diseases. Converging evidence suggested that acute stress is associated with increase of excitatory transmission in certain forebrain areas. Aim of this work was to investigate the mechanism whereby acute stress increases glutamate release, and if therapeutic drugs prevent the effect of stress on glutamate release.Methodology/findingsRats were chronically treated with vehicle or drugs employed for therapy of mood/anxiety disorders (fluoxetine, desipramine, venlafaxine, agomelatine) and then subjected to unpredictable footshock stress. Acute stress induced marked increase in depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex in superfusion, and the chronic drug treatments prevented the increase of glutamate release. Stress induced rapid increase in the circulating levels of corticosterone in all rats (both vehicle- and drug-treated), and glutamate release increase was blocked by previous administration of selective antagonist of glucocorticoid receptor (RU 486). On the molecular level, stress induced accumulation of presynaptic SNARE complexes in synaptic membranes (both in vehicle- and drug-treated rats). Patch-clamp recordings of pyramidal neurons in the prefrontal cortex revealed that stress increased glutamatergic transmission through both pre- and postsynaptic mechanisms, and that antidepressants may normalize it by reducing release probability.Conclusions/significanceAcute footshock stress up-regulated depolarization-evoked release of glutamate from synaptosomes of prefrontal/frontal cortex. Stress-induced increase of glutamate release was dependent on stimulation of glucocorticoid receptor by corticosterone. Because all drugs employed did not block either elevation of corticosterone or accumulation of SNARE complexes, the dampening action of the drugs on glutamate release must be downstream of these processes. This novel effect of antidepressants on the response to stress, shown here for the first time, could be related to the therapeutic action of these drugs.

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Dataset Information

Flow Synthesis and Biological Studies of an Analgesic Adamantane Derivative That Inhibits P2X7-Evoked Glutamate Release.

Publications

Flow Synthesis and Biological Studies of an Analgesic Adamantane Derivative That Inhibits P2X7-Evoked Glutamate Release.

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