Synthesis of enantiomerically pure HIP-A and HIP-B and investigation of their activity as inhibitors of excitatory amino acid transporters

Andrea Pinto, Paola Conti, Marco De Amici, Lucia Tamborini, Giovanni Grazioso, Simona Colleoni, Tiziana Mennini, Marco Gobbi, Carlo De Micheli

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The present report deals with the synthesis of the two couples of enantiomers (+)-(3aS,4R,6aS)-/(-)-(3aR,4S,6aR)-3-hydroxy-3a,4,6,6a-tetrahydro-pyrrol o[3,4-d]isoxazole-4-carboxylic acid [(+)-HIP-A and (-)-HIP-A] and (+)-(3aS,6S,6aS)-/(-)-(3aR,6R,6aR)-3-hydroxy-3a,4,6,6a-tetrahydro-pyrrol o[3,4-d]isoxazole-6-carboxylic acid [(+)-HIP-B and (-)-HIP-B], and the investigation of their inhibitory activity at EAATs. When tested in a [3H]d-aspartate uptake assay on native EAATs present in rat brain synaptosomal fractions, (-)-HIP-A and (+)-HIP-B turned out to be considerably more potent than their enantiomers; in particular, (-)-HIP-A showed an eudismic ratio (ER) higher than 100. Molecular modeling investigations gave clues with regard to the key amino acid residues involved in the binding with our inhibitors and provided explanations for the observed stereoselectivity.

Original languageEnglish
Pages (from-to)867-875
Number of pages9
JournalTetrahedron: Asymmetry
Volume19
Issue number7
DOIs
Publication statusPublished - Apr 17 2008

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Isoxazoles
Amino Acid Transport Systems
transporter
hot isostatic pressing
Excitatory Amino Acids
Hot isostatic pressing
Carboxylic Acids
inhibitors
amino acids
Amino acids
synthesis
Aspartic Acid
Enantiomers
Amino Acids
enantiomers
Carboxylic acids
carboxylic acids
Brain
aspartates
Stereoselectivity

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Organic Chemistry
  • Materials Chemistry
  • Drug Discovery

Cite this

Synthesis of enantiomerically pure HIP-A and HIP-B and investigation of their activity as inhibitors of excitatory amino acid transporters. / Pinto, Andrea; Conti, Paola; De Amici, Marco; Tamborini, Lucia; Grazioso, Giovanni; Colleoni, Simona; Mennini, Tiziana; Gobbi, Marco; De Micheli, Carlo.

In: Tetrahedron: Asymmetry, Vol. 19, No. 7, 17.04.2008, p. 867-875.

Research output: Contribution to journalArticle

Pinto, Andrea ; Conti, Paola ; De Amici, Marco ; Tamborini, Lucia ; Grazioso, Giovanni ; Colleoni, Simona ; Mennini, Tiziana ; Gobbi, Marco ; De Micheli, Carlo. / Synthesis of enantiomerically pure HIP-A and HIP-B and investigation of their activity as inhibitors of excitatory amino acid transporters. In: Tetrahedron: Asymmetry. 2008 ; Vol. 19, No. 7. pp. 867-875.
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