Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue
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Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid : a novel conformationally restricted glutamic acid analogue. / Bunch, Lennart; Liljefors, Tommy; Greenwood, Jeremy R; Frydenvang, Karla Andrea; Bräuner-Osborne, Hans; Krogsgaard-Larsen, Povl; Madsen, Ulf.
In: Journal of Organic Chemistry, Vol. 68, No. 4, 2003, p. 1489-95.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid
T2 - a novel conformationally restricted glutamic acid analogue
AU - Bunch, Lennart
AU - Liljefors, Tommy
AU - Greenwood, Jeremy R
AU - Frydenvang, Karla Andrea
AU - Bräuner-Osborne, Hans
AU - Krogsgaard-Larsen, Povl
AU - Madsen, Ulf
PY - 2003
Y1 - 2003
N2 - 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).
AB - 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).
KW - Aza Compounds
KW - Dicarboxylic Acids
KW - Glutamic Acid
KW - Inhibitory Concentration 50
KW - Kainic Acid
KW - Magnetic Resonance Spectroscopy
KW - Molecular Conformation
KW - Molecular Mimicry
KW - Molecular Structure
KW - Norbornanes
KW - Receptors, Glutamate
KW - Stereoisomerism
KW - Structure-Activity Relationship
KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
U2 - 10.1021/jo026509p
DO - 10.1021/jo026509p
M3 - Journal article
C2 - 12585893
VL - 68
SP - 1489
EP - 1495
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
SN - 0022-3263
IS - 4
ER -
ID: 40371578