'Atypical' neuromodulatory profile of glutapyrone, a representative of a novel 'class' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds: In vitro and in vivo studies

Ilga Misane, Vija Klusa, Maija Dambrova, Skaidrite Germane, Gunars Duburs, Egils Bisenieks, Roberto Rimondini, Sven Ove Ögren

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Glutapyrone, a disodium salt of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)-glutaric acid, is a representative of a novel 'class' of amino acid-containing 1,4-dihydropyridine (DHP) compounds developed at the Latvian Institute of Organic Synthesis, Riga, Latvia. Conceptually, the glutapyrone molecule can be regarded as a dipeptide-mimicking structure formed by the 'free' amino acid (glutamate) moiety and 'crypto' (built into the DHP cycle) amino acid ('GABA') elements. Both of these amino acids are joined by the peptide bond. This compound unlike classical DHPs lacks calcium antagonistic or agonistic properties. Our previous studies revealed a profound and long-term anticonvulsant, stress-protective and neurodeficit-preventive activities of glutapyrone. In view of structural properties the role of glutamatergic mechanisms in the mediation of central effects of glutapyrone was considered. In the present study glutapyrone at the concentration range of 1 μM-1 mM failed to effect both NMDA ([3H]TCP) and non-NMDA ([3H]KA and [3H]AMPA) receptor ligand binding in the rat cortical membranes in vitro. The compound markedly enhanced motor hyperactivity induced by the NMDA antagonist PCP and the dopamine releasing compound d-amphetamine in the rats. Glutapyrone displayed activity in a variety of animal models relevant for affective/depressive disorders in humans i.e. reserpine-induced ptosis and hypothermia, forced swimming test and open field test. These data indicate that the unusually 'broad' pharmacological spectrum of glutapyrone might involve concomitant actions on multiple neurotransmitter systems, particularly, GABA-ergic and the catecholamines. It is discussed whether these functional properties are secondary to action on intracellular events, predominantly, G protein-related since glutapyrone appears to lack direct interactions with a number of receptors including ionotropic glutamate and GABA(A)/Bzd receptors. Copyright (C) 1998 Elsevier Science B.V./ECNP.

Original languageEnglish
Pages (from-to)329-347
Number of pages19
JournalEuropean Neuropsychopharmacology
Volume8
Issue number4
DOIs
Publication statusPublished - 1 Dec 1998
Externally publishedYes

Keywords

  • 1,4-Dihydropyridines
  • Biogenic amine transporters
  • CNS-targeting drugs
  • Dipeptides
  • G proteins
  • GABA
  • Glutamate
  • Glutapyrone
  • Receptors

Field of Science

  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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