TY - JOUR
T1 - 'Atypical' neuromodulatory profile of glutapyrone, a representative of a novel 'class' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds
T2 - In vitro and in vivo studies
AU - Misane, Ilga
AU - Klusa, Vija
AU - Dambrova, Maija
AU - Germane, Skaidrite
AU - Duburs, Gunars
AU - Bisenieks, Egils
AU - Rimondini, Roberto
AU - Ögren, Sven Ove
N1 - Funding Information:
This work was supported in part by grants from the Royal Swedish Academy of Sciences, Project N 1375; The Karolinska Institute International Research and Training Programme (KIRT; Reg, no: Latvia 10 (1995) and Reg, no: Latvia 13 (1996)); Nordic Council of Ministers, the Centre for International Mobility (CIMO) and Latvian Science Council, grant No. 96.0698. The authors gratefully acknowledge the assistance of Assoc. Prof. Leena Tuomisto (Department of Pharmacology and Toxicology, University of Kuopio, Finland).
PY - 1998/12/1
Y1 - 1998/12/1
N2 - 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.
AB - 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.
KW - 1,4-Dihydropyridines
KW - Biogenic amine transporters
KW - CNS-targeting drugs
KW - Dipeptides
KW - G proteins
KW - GABA
KW - Glutamate
KW - Glutapyrone
KW - Receptors
UR - http://www.scopus.com/inward/record.url?scp=0032402591&partnerID=8YFLogxK
U2 - 10.1016/S0924-977X(97)00097-7
DO - 10.1016/S0924-977X(97)00097-7
M3 - Article
C2 - 9928926
AN - SCOPUS:0032402591
SN - 0924-977X
VL - 8
SP - 329
EP - 347
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 4
ER -
