C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model.

Mirosław Zagaja,Magdalena Chrościńska-Krawczyk,Aleksandra Szewczyk,Joanna Szala-Rycaj,Krzysztof Kamiński,Michał Abram,Marta Andres-Mach,Grzegorz Raszewski

doi:10.3390/molecules26113144

Abstract

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.

Highlights

IntroductionOne of the most common diseases of the nervous system, belongs to a group of social diseases
Epilepsy, one of the most common diseases of the nervous system, belongs to a group of social diseases
We evaluated C-11 influence on cognitive functions, neurodegeneration, and neurogenesis process in mice after chronical treatment in C57BL/6 mice

Summary

Introduction

One of the most common diseases of the nervous system, belongs to a group of social diseases. The ineffectiveness of monotherapy with two consecutive drugs from the same group is the basis for the introduction of polytherapy with two or more the same group is the basis for the introduction of polytherapy with two or mor preferably with different mechanisms of action [4,5,6]. Such therapy, an increased risk of side effects. There is an urgent need to develop a new class of active compoun anticonvulsant and neuroprotective properties while being non-toxic. Over the past few years,Aoumr otenamg ahaws fiodceusreadnognetohef sseuacrhchsfuorbnsetawnscuebsstiasntchese, 2bo-(t2h,n5a-dtuiroaxl oanpdysryrnotlhidetiinc,-1-yl) p tmhaitdheavdeesruivchatpirvoep,eCrti-e1s1, a(nfdormmayerhlayvKe aAm-1a1gn) i(fFyiingguerfefe1ct).onThcoims cmoemrcipalolyuunsdedisAaEDhsy,brid su increasing their anticonvulsant activity [7,8,9,10,11,12,13,14]

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