Some aspects in the search for anticonvulsants (a review)

Abstract

Functional organization of the central nervous system (CNS) relies upon a fine interplay between two principal processes involved in nervous activity: excitation and inhibition. Violation of this interaction leads to the development of cerebral pathologies. Both the excitation and inhibition processes are mediated by intercell and intracell chemical neurotransmitters (endogenous ligands). In particular, interference with the neuromediator function of only g-aminobutyric acid (GABA) causes a number of pathologies, primarily convulsive states, determining the symptomatics of disorders such as epilepsy, drug intoxication (strychnine, corazole, bemegride, novocain, organophosphorus compounds, insecticides, etc.), infectious diseases (meningitis, toxic influenza, tetanus, etc.), cerebral traumas, brain edemas, and others. In practice, such convulsions can be arrested using drugs belonging to various pharmacological groups, including pure anticonvulsants, barbiturates, bromides, tranquilizers, hypnotics, etc., which are ca-pable of preventing the development or decreasing the intensity of convulsions, reducing the frequency of attacks, or eliminating the accompanying disturbances (loss of consciousness, behavioral and vegetative disorders, etc.).However, the group of anticonvulsants presently administered in practice contains no one highly effective drug of universal use. This is related not only to the variety of forms of the convulsive states, but also to the complexity of interactions between neuromediator systems, primarily those of inhibiting (GABA) and exciting amino acids [1 -5]. The continuous search for new anticonvulsants (see, e.g., [6 -20]) needs no additional justification. This paper addresses certain features and rules in the search for compounds possessing anticonvulsant activity.Biochemical disorders in CNS, which are capable of inducing the development of convulsions, include changes in (i) the transmembrane concentration gradients of sodium, potassium, calcium, and chlorine ions (factors providing for the membrane rest and action potentials), (ii) the energy balance in neurons, and (iii) the level and metabolism of synaptic mediators including GABA, glutamic and asparagic acids (ex-

Structural Features of the Binding Site for Diphenin and other Anticonvulsants belonging to the Group of Sodium Channel Blockers

“…An alternative learning set formed based on the therapeutic principle involves a much broader range of compounds belonging to various chemical classes [1 -48]. Therefore, it was expedient to perform TCA using the latter learning set, from which a series of like structures [3] was selected with allowance for the structural and functional features and the laws of formation of the molecular framework of anticonvulsants belonging to the group of sodium channel blockers.…”

“…(i) The interaction of anticonvulsants (ligands) with receptors involves atoms with unshared electron pairs, p bonds, or aromatic sextets in pharmacophore fragments (PPFs) capable of forming hydrogen bonds (H-bonds) [3,48]. The mutual spatial arrangement of PPFs in the biologically active conformations must be identical for all molecules under consideration.…”