Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids.
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.
Conti
Paola
P
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
De Amici
Marco
M
Joppolo Di Ventimiglia
Samuele
S
Stensbøl
Tine B
TB
Madsen
Ulf
U
Bräuner-Osborne
Hans
H
Russo
Emilio
E
De Sarro
Giovambattista
G
Bruno
Giuseppe
G
De Micheli
Carlo
C
D024342:Amino Acids, Acidic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000600:Amino Acids, Dicarboxylic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008968:Molecular Conformation; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
C476141:5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta(d)isoxazole-3,5-dicarboxylic acid; D024342:Amino Acids, Acidic; D000600:Amino Acids, Dicarboxylic; D000927:Anticonvulsants; D003998:Dicarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D006574:Heterocyclic Compounds, 2-Ring; D007555:Isoxazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1