First enantiospecific synthesis of a 3,4-dihydroxy-L-glutamic acid [(3S,4S)-DHGA], a new mGluR1 agonist.
The first synthesis of one of the 4 possible stereoisomers of 3,4-dihydroxy-L-glutamic acid ((3S,4S)-DHGA 3), a natural product of unknown configuration, is described. The synthesis is based on the Lewis acid catalyzed reaction of benzyl alcohol with a D-ribose-derived 2,3-aziridino-gamma-lactone 4-benzyl carboxylate (6). Preliminary pharmacological studies showed that (3S,4S)-3 is an agonist of metabotropic glutamate receptors of type 1 (mGluR1) and a weak antagonist of mGluR4 but has no discernible activity with respect to mGluR2. This activity profile can be rationalized by fitting extended conformations of (3S,4S)-3 in proposed models of each of these receptor subtypes.
Dauban
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P
Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
de Saint-Fuscien
C
C
Acher
F
F
Prézeau
L
L
Brabet
I
I
Pin
J P
JP
Dodd
R H
RH
D002460:Cell Line; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000032:analysis; D008958:Models, Molecular; D008968:Molecular Conformation; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013237:Stereoisomerism; D010738:Type C Phospholipases / Q000378:metabolism
C404740:3,4-dihydroxyglutamic acid; D005971:Glutamates; D007295:Inositol Phosphates; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D010738:Type C Phospholipases