Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates: Synthesis, in vitro pharmacology, and modeling

László Héja, Ilona Kovács, E. Szárics, Maria Incze, Eszter Temesváriné-Major, Gábor Dörnyei, M. Kajtár-Peredy, E. Gács-Baitz, Csaba Szántay, J. Kardos

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Three of twelve secoergoline derivatives (Z ethyl 4-[(ethoxycarbonylmethyl) methylamino]-2-methyl-3-phenylpent-2-enoate, 8; ethyl 1,6-dimethyl-3-oxo-5- phenyl-1,2,3,6-tetrahydropyridine-2-carboxylate, 9; Z methyl 4-[(methoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate, 11), containing bioisosteric sequences of GABA and Glu, inhibited both GABA and Glu transport through cerebrocortical membranes specifically. Compounds 8,9, and 11 appeared to be equipotent inhibitors of GABA and Glu transport with IC50 values between 270 and 1100 μM, whereas derivatives 1-7, 10, and 12 were without effects. In the presence of GABA and Glu transport-specific nontransportable inhibitors, inhibition of GABA and Glu transport by 8, 9, and 11 proceeded in two phases. The two phases of inhibition were characterized by IC50 values between 4 and 180 nM and 360-1020 μM and different selectivity sequences. These findings may indicate the existence of some mechanism possibly mediated by a previously unrecognized GABA-Glu transporter. Derivatives with the cis, but not the trans configuration of bulky ester groups (8 vs 7 and 11 vs 12) showed significant inhibitory effect (IC50 values of 270 μM vs ≫ 1000 μM and 1100 μM vs ≫ 1000 μM on GABA transport, respectively). The cis-trans selectivity can be explained by docking these secoergolines in a three-dimensional model of the second and third transmembrane helices of GABA transporter type 1.

Original languageEnglish
Pages (from-to)5620-5629
Number of pages10
JournalJournal of Medicinal Chemistry
Volume47
Issue number23
DOIs
Publication statusPublished - Nov 4 2004

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gamma-Aminobutyric Acid
Rats
Glutamic Acid
Brain
Pharmacology
Derivatives
GABA Plasma Membrane Transport Proteins
Inhibitory Concentration 50
N-(gamma-aminobutyryl)glutamic acid
In Vitro Techniques
Esters
Membranes

ASJC Scopus subject areas

  • Organic Chemistry

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Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates : Synthesis, in vitro pharmacology, and modeling. / Héja, László; Kovács, Ilona; Szárics, E.; Incze, Maria; Temesváriné-Major, Eszter; Dörnyei, Gábor; Kajtár-Peredy, M.; Gács-Baitz, E.; Szántay, Csaba; Kardos, J.

In: Journal of Medicinal Chemistry, Vol. 47, No. 23, 04.11.2004, p. 5620-5629.

Research output: Contribution to journalArticle

Héja, László ; Kovács, Ilona ; Szárics, E. ; Incze, Maria ; Temesváriné-Major, Eszter ; Dörnyei, Gábor ; Kajtár-Peredy, M. ; Gács-Baitz, E. ; Szántay, Csaba ; Kardos, J. / Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates : Synthesis, in vitro pharmacology, and modeling. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 23. pp. 5620-5629.
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T1 - Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates

T2 - Synthesis, in vitro pharmacology, and modeling

AU - Héja, László

AU - Kovács, Ilona

AU - Szárics, E.

AU - Incze, Maria

AU - Temesváriné-Major, Eszter

AU - Dörnyei, Gábor

AU - Kajtár-Peredy, M.

AU - Gács-Baitz, E.

AU - Szántay, Csaba

AU - Kardos, J.

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AB - Three of twelve secoergoline derivatives (Z ethyl 4-[(ethoxycarbonylmethyl) methylamino]-2-methyl-3-phenylpent-2-enoate, 8; ethyl 1,6-dimethyl-3-oxo-5- phenyl-1,2,3,6-tetrahydropyridine-2-carboxylate, 9; Z methyl 4-[(methoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate, 11), containing bioisosteric sequences of GABA and Glu, inhibited both GABA and Glu transport through cerebrocortical membranes specifically. Compounds 8,9, and 11 appeared to be equipotent inhibitors of GABA and Glu transport with IC50 values between 270 and 1100 μM, whereas derivatives 1-7, 10, and 12 were without effects. In the presence of GABA and Glu transport-specific nontransportable inhibitors, inhibition of GABA and Glu transport by 8, 9, and 11 proceeded in two phases. The two phases of inhibition were characterized by IC50 values between 4 and 180 nM and 360-1020 μM and different selectivity sequences. These findings may indicate the existence of some mechanism possibly mediated by a previously unrecognized GABA-Glu transporter. Derivatives with the cis, but not the trans configuration of bulky ester groups (8 vs 7 and 11 vs 12) showed significant inhibitory effect (IC50 values of 270 μM vs ≫ 1000 μM and 1100 μM vs ≫ 1000 μM on GABA transport, respectively). The cis-trans selectivity can be explained by docking these secoergolines in a three-dimensional model of the second and third transmembrane helices of GABA transporter type 1.

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