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

Abstract

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 (4 R,9a S) 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 ED 50 values comparable to the reference drug Levetiracetam. Derivatives (4 S,9a R)-6 and (4 R,9a R)-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.