Characterization of the anticonvulsant profile of valpromide derivatives

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Abstract

The antiepileptic activity of nine derivatives of valpromide is discussed. They comply with a pharmacophore model that establishes the essential structural and electronic features responsible for the protection against the MES test. The model results from the comparison of 17 structures, using density functional methodologies combined with an active analog approach. The derivatives of valpromide have been tested for anticonvulsant activity in mice. These compounds displayed a phenytoin-like profile, being active in the MES test and inactive in the PTZ test. 4-(Valproylamido)benzenesulfonamide is the most active compound, with an ED50 of 53 μmol/kg and no neurotoxicity at doses up to 1000 μmol/kg. The pharmacological behavior of the drugs points to a sodium channel blocking effect as one of the associated mechanisms. This mechanism was tested positive for N-ethylvalpromide through its competition with the binding of [3H]batrachotoxin-A-20α-benzoate to the voltage-dependent sodium channels from rat brain synaptosomes.

Introduction

Among the different neurological disorders that affect human condition, epilepsy has been largely studied during the last century,[1], [2], [3], [4] becoming a dynamic research field in recent years.[4], [5], [6], [7], [8], [9], [10], [11], [12], [13] It describes disorders characterized by recurrent seizure attacks due to synchronous neuronal firing. The main drawback related to its therapy is associated with the fact that antiepileptic drugs (AEDs) fail to control seizures in 20–25% of patients.[9], [10], [11], [14], [15] Moreover, even the new generation of AEDs causes sizeable side effects, which include ataxia, diplopia, mental dulling, rash, blood dyscrasias, and hepatotoxicity.7 Thus, new AEDs with better safety, less toxicity, and higher efficacy in difficult-to-control patients are urgently needed.8

The broad spectra of mechanisms, which may occur during drug action in the epileptic patient, include, among others, voltage-dependent blockade of Na+ channels, modulation of GABA synthesis, or degradation, inhibition of cellular GABA uptake, modulation of GABAA receptors, modulation of various excitatory amino acid receptors, and modulation of adenosine metabolism.[3], [4], [9] For this reason, several seizure models have been developed to evaluate the anticonvulsant (AC) activity during the research process. Among them, the maximal electroshock (MES) and the subcutaneous pentylenetetrazol (PTZ) tests are the most widely used.2 These models respond well to neuronal voltage-gated sodium channel (VGSC) inhibitors and gabaergic compounds, respectively.[5], [7]

A large number of ligands that are presently marketed (or in the process of being marketed) as AEDs exhibit a similar pharmacological profile, being quite potent in the MES test and inactive in the PTZ test. This is the case of the widely used phenytoin (PHE), as well as carbamazepine (CZ), topiramate (TOP), lamotrigine (LAM), zonisamide (ZON), ralitoline (RAL), and oxcarbazepine (OCZ).[4], [5], [9], [15], [16], [17] The drugs sharing the PHE-like profile of activity are accepted today to prevent seizures because they block Na+ channels in the brain.[7], [15] Na+ channel blockers are front-runners in the treatment of epilepsy. This mechanism is not, however, unique for the above mentioned drugs. As an example, the variety of molecular actions displayed by valproic acid (VPA) includes Na+ channel blockade, increase of GABA levels in the brain by glutamate decarboxylase activation and GABA transaminase inhibition, increase of postsynaptic GABA responses, direct membrane effects on the neurons, and blockade of Ca++ channels.[9], [15], [16], [18]

In spite of the large amount of attempts of postulating a general pharmacophore for the antiepileptic activity, only one has been reported, to our knowledge, for the Na+ channel blocking activity of dissimilar antiepileptic compounds.19 The model reported is based on the structural comparison of CZ, PHE, LAM, ZON, and rufinamide (RUF), and identifies three groups of different characteristics that should be present, at well-defined distances, in order for the structures to be active. These different groups involve an aryl ring, an electron donor atom and a second donor atom which, close to an NH group, defines a hydrogen bond acceptor/donor unit. On the other hand, several model pharmacophores have been developed from the comparison of complexes that belong to a given family. Some of them bear some similarities in relation to the position of H-bond donor/acceptor and lipophilic groups. In this way, from the comparative analysis of compounds structurally related to N-benzylamides of γ-hydroxybutyric acid (GMB),20 the requirements for activity have been associated with the presence of an N-benzylamide fragment, an aryl ring, and a H-bond donor group located between them (see Fig. 1).

For the case of ureylenes and semicarbazones, a model pharmacophore has been proposed, which points to the existence of an H-bonding site located between two hydrophobic areas (Fig. 2). The H-bonding site has been further disclosed in H-bonding and electron donor groups.21

Computational analysis has also contributed in other cases to design novel antiepileptic ligands, but the studies were limited to compounds of a given family.22 We have recently analyzed several AEDs, which are recognized to bind to Na+ channels.23 On the basis of this analysis, we have proposed a pharmacophore that, showing some similarities with the one previously described,19 mainly differs in the necessity of an electron donor group. According to our analysis, based on a larger set of structures, the presence of an acceptor/donor unit comprising two closely located H-donor–acceptor groups, together with a lipophilic portion, defines enough conditions to attain activity.

On the basis of this pattern, we have considered a set of AEDs, structurally related to VPA. They bear a high degree of flexibility and we speculate this might help to accommodate the receptor pocket more easily. Showing a PHE-like profile, they manifest higher anti-MES potency than the parent compound. As a further test of the relation between the PHE-like activity and the Na+ channel blocking capability, in vitro tests have been performed for a representative member of the newly designed set, which meets the requirements of potency and solubility.

We present, in the first part of this article, a validation of the previous pharmacophore, using a training set that extends the previous one, including AEDs developed in previous years. Some of them derive from the already marketed PHE and LAM,[22], [24], [25] but also structures as diverse as γ-butyrolactams, semicarbazides, and 3-aminopyrrole are included.[19], [26], [27], [28], [29], [30] The second part of the article deals with the synthesis and biological evaluation of the VPD-related AEDs, thoroughly discussing their pharmacological profile.

Section snippets

Pharmacophore identification

The activity data for the compounds that define the training set (Fig. 3, Table 1) quantify their response to the MES and PTZ tests. The majority of them show a PHE-like profile, being active against the MES test and inactive against the PTZ test. Some of them (felbamate––FLB, remacemide––RMC, ethosuximide––ETH, vinpocetina––VIN) are also active in the PTZ test. They have been selected on the basis of their common capability of blocking the VGSC, as either established or newer drugs that have

Conclusions

The pharmacological profile of a set of valpromide derivatives has been extensively analyzed. The pharmacological behavior resembles PHE being active against MES and inactive against PTZ. The derivatives comply with the requirements imposed by a pharmacophore proposed for the anti-MES activity. The pharmacophoric pattern, on the other hand, has been shown to represent the structural and electronic features compatible with a Na+ channel blocking mechanism.

SUVPD-1 appears as the most potent

Chemistry

1H and 13C NMR spectra were recorded on a Bruker AC-200 spectrometer with tetramethylsilane as an internal standard. Melting points were determined on an Electrothermal IA6304 apparatus and are uncorrected. Elemental analyses were measured on a Carlo Erba EA 1108. Solvents were purified and dried by standard procedures. The evolution of the reaction was monitored by TLC (thin layer chromatography). All TLC data were determined using aluminum sheets with silica gel 60 F254 (Merck-Darmstadt,

Acknowledgements

G.L.E. has performed this research as a member of the Consejo Nacional de Investigaciones Cientı́ficas y Técnicas de la República Argentina (CONICET), L.E.B.-B. and S.Ch.M. are researchers of the Facultad de Ciencias Exactas, Universidad Nacional de La Plata. S.M.T. is a fellowship holder of CONICET. This work was supported in part through grants from Agencia de Promoción Cientı́fica y Tecnológica (PICT 98-06-03237) CONICET (PIP No 02207 Res 1478) and Universidad Nacional de La Plata, Argentina.

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