Synthesis and biological activity of the N-alkyl derivatives of ibotenic acid

Abstract

An important current problem in the modern drug chemistry and neuropharmacology is the synthesis and characterization of new compounds capable of acting upon the system of excitatory amino acids (EAAs) in the CNS of mammals. The EAA-ergic structures play an important role in the regulation of physiological and pathophysiological processes in the brain, which is confirmed by the fact that dicarboxylic acids act as mediators in associative, emotional, vegetative, and some other CNS functions [1][2][3]. The EAA receptors can be divided into two groups. The first group includes ionotropic receptors of three types-N-methyl-D-aspartic acid (NMDA) type, 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) type, and kainate type. The second group contains the metabotropic receptors (mGluR 1 -8) [4 -6].Among the large number of natural amino acids, which usually exhibit the properties of nonselective agonists of EAA receptors, there is one-2-amino-2-(3-hydroxy-5-isoxazolyl)acetic (or ibotenie) acid (I)-that is-worthy of special attention. Acid I, originally isolated from Amanita muscaria fungi, can be considered as a conformationally rigid analog ofglutamic acid, in which the 3-hydroxyisoxazole cycle serves a bioisosteric fragment for the 7-carboxyl group. This acid interacts predominantly with EAA receptors of the NMDA type, but is capable of activating some other types of EAA receptors as well [6].Acid 1 was used in many works as an initial structure in the synthesis of ligands for various EAA receptors. Extension of the methylene chain between the glycine fragment and the isoxazole cycle by adding a methylene group (homoibotenic acid) [7] and the transfer of this group in the ring toward the C4 atom (AMPA and its analogs) leads to increasing selectivity with respect to EAA receptors of the AMPA type [8,9]. On the other hand, compounds obtained upon extension of the alkyl chain of the AMPA molecule-2-amino4-(3-hy-