Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue.
The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2.2.1]bicyclic intermediate was investigated. In this transformation, the catalytic methodology of Wilkinson's/catechol borane proved superior to stoichiometric borane or dialkyl borane reagents, in terms of higher diastereomeric excess and chemical yield. To our surprise (+/-)-1 did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid).
Bunch
Lennart
L
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark. lebu@dfh.dk
Liljefors
Tommy
T
Greenwood
Jeremy R
JR
Frydenvang
Karla
K
Bräuner-Osborne
Hans
H
Krogsgaard-Larsen
Povl
P
Madsen
Ulf
U
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007608:Kainic Acid / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D018716:Molecular Mimicry; D015394:Molecular Structure; D009636:Norbornanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D017470:Receptors, Glutamate / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
C477981:2-azanorbornane-3-exo,5-endo-dicarboxylic acid; D001372:Aza Compounds; D003998:Dicarboxylic Acids; D009636:Norbornanes; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid