Rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue

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

SN - 0022-3263

VL - 68

SP - 1489

EP - 1495

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 4

ER -