Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 2: Perhydropyrido[1,2-a]pyrazines

A new series of chiral pyrido[1,2-a]pyrazine derivatives was synthesised and evaluated in in vivo animal models of epilepsy. A significant influence of the stereochemistry of the pyrido[1,2-a]pyrazine framework on the pharmacological activity was observed. Compounds with (4R,9aS) absolute configuration proved inactive, whereas other stereoisomers exhibited markedly dissimilar spectra of anti-seizure efficacy in the maximal electroshock seizure (MES), subcutaneous Metrazol seizure (scMET) and Pilocarpine-induced status prevention (PISP) tests. Importantly, the investigated agents revealed high potency in the 6 Hz model, with the ED50 values comparable to the reference drug Levetiracetam. Derivatives (4S,9aR)-6 and (4R,9aR)-6 emerged as promising new lead structures, the former having a broad spectrum of anticonvulsant activity and the latter showing high potency in 6 Hz and PISP models.

A series of chiral pyrido[1,2-a]pyrazine derivatives was evaluated as potential anticonvulsant agents. A very pronounced influence of stereochemistry on the in vivo anti-seizure activity was observed.Figure optionsDownload as PowerPoint slideHighlights
► A series of novel derivatives of pyrido[1,2-a]pyrazine was synthesised.
► The obtained compounds were screened in in vivo animal models of epilepsy.
► The stereochemistry of the heterocyclic core largely affected the activity profiles.
► Compound (4S,9aR)-6 was most potent in various models of epilepsy.
► Isomer (4R,9aR)-6 showed high activity in 6 Hz test with no concomitant neurotoxicity.