title: 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 (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 6Hz model, with the ED(50) 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 6Hz and PISP models.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland. maciej.dawidowski@wum.edu.pl
authors.forename: Maciej
authors.initials: M
authors.lastname: Dawidowski
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
authors.forename: Andrzej
authors.initials: A
authors.lastname: Chodkowski
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kleps
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001681:Biological Assay; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009904:Optical Rotation; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D054659:Diketopiperazines; D011719:Pyrazines