S. Kulikov, V. V. Grigor’ev, V. V. Ragulin
Jul 1, 1997
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Journal
Pharmaceutical Chemistry Journal
Abstract
Aspartic and glutamic acids are the major mediators of excitation in both human and mammalian central nervous system (CNS), and play an important role in the function of the CNS in the intact organism and during the development of various pathological states. As is known, antagonists of the N-methyl-D-aspartic (NMDA) acid receptor, a subtype of the glutamic receptors, possess pronounced anticonvulsive properties. The NMDA receptor antagonists were found in a series of phosphorus-containing aminocarboxylic acids and among dipeptides obtained on the basis of glutamic and aspartic acids [2, 3]. 2-Amino-5-phosphonovaleric acid (AP5) is a selective antagonist of the NMDA receptor and also exhibits anticonvulsive activity [4 6]. This article is devoted to the synthesis and study of the anticonvulsive activity of D,L-AP5 based peptides (I, H). A key intermediate product in the synthesis of dipeptides is the dibenzyl ester of D,L-AP5 obtained in the form ofptoluenesulfonate (III) by interaction of D,L-AP5 with excess benzyl alcohol in the presence ofp-toluenesulfonic acid [7]. Interactions of compound III with N-hydrosuccinimide ester of N-benzyloxycarbonyl phenylalanine (IV) [8] and p-nitrophenyl ester oftricarbobenzoxy arginine (V) [9] under the conditions described in [ 10] led to the formation ofbenzyl ester of N-benzyloxycarbonyl-L-phenylalanyl-D,L-AP5 (VI) and benzyI ester o f tricarbobenzoxy-L-arginyl-D,L-AP5 (VII). Reduction of VI and VII by the method developed in [1 I, 12] yielded the target peptides I and II.