Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids

Paola Conti; Marco De Amici; Samuele Joppolo Di Ventimiglia; Tine B Stensbøl; Ulf Madsen; Hans Bräuner-Osborne; Emilio Russo; Giovambattista De Sarro; Giuseppe Bruno; Carlo De Micheli

doi:10.1021/jm0308085

Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids

Paola Conti, Marco De Amici, Samuele Joppolo Di Ventimiglia, Tine B Stensbøl, Ulf Madsen, Hans Bräuner-Osborne, Emilio Russo, Giovambattista De Sarro, Giuseppe Bruno, Carlo De Micheli

32 Citations (Scopus)

Abstract

Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	46
Issue number	14
Pages (from-to)	3102-8
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm0308085
Publication status	Published - 3 Jul 2003

Keywords

Amino Acids, Acidic
Amino Acids, Dicarboxylic
Animals
Anticonvulsants
CHO Cells
Cerebral Cortex
Cricetinae
Crystallography, X-Ray
Dicarboxylic Acids
Excitatory Amino Acid Agonists
Excitatory Amino Acid Antagonists
Heterocyclic Compounds, 2-Ring
Isoxazoles
Male
Mice
Mice, Inbred DBA
Molecular Conformation
Rats
Receptors, Metabotropic Glutamate
Receptors, N-Methyl-D-Aspartate
Stereoisomerism

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title = "Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids",

abstract = "Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.",

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author = "Paola Conti and {De Amici}, Marco and {Joppolo Di Ventimiglia}, Samuele and Stensb{\o}l, {Tine B} and Ulf Madsen and Hans Br{\"a}uner-Osborne and Emilio Russo and {De Sarro}, Giovambattista and Giuseppe Bruno and {De Micheli}, Carlo",

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doi = "10.1021/jm0308085",

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AU - Conti, Paola

AU - De Amici, Marco

AU - Joppolo Di Ventimiglia, Samuele

AU - Stensbøl, Tine B

AU - Madsen, Ulf

AU - Bräuner-Osborne, Hans

AU - Russo, Emilio

AU - De Sarro, Giovambattista

AU - Bruno, Giuseppe

AU - De Micheli, Carlo

PY - 2003/7/3

Y1 - 2003/7/3

N2 - Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.

AB - Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.

KW - Amino Acids, Acidic

KW - Amino Acids, Dicarboxylic

KW - Animals

KW - Anticonvulsants

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KW - Cricetinae

KW - Crystallography, X-Ray

KW - Dicarboxylic Acids

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KW - Excitatory Amino Acid Antagonists

KW - Heterocyclic Compounds, 2-Ring

KW - Isoxazoles

KW - Male

KW - Mice

KW - Mice, Inbred DBA

KW - Molecular Conformation

KW - Rats

KW - Receptors, Metabotropic Glutamate

KW - Receptors, N-Methyl-D-Aspartate

KW - Stereoisomerism

U2 - 10.1021/jm0308085

DO - 10.1021/jm0308085

M3 - Journal article

C2 - 12825948

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EP - 3108

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 14

ER -

Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids

Abstract

Keywords

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