Glutamate receptor ligands: Synthesis, stereochemistry, and enantiopharmacology of methylated 2-aminoadipic acid analogs

Authors

  • Mette Guldbrandt,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Tommy N. Johansen,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Karla Frydenvang,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Hans Bräuner-Osborne,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Tine B. Stensbøl,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Birgitte Nielsen,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Rolf Karla,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Flavio Santi,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Povl Krogsgaard-Larsen,

    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
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  • Ulf Madsen

    Corresponding author
    1. Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark
    • Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark
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Abstract

Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA) analogs, and the synthesis, stereochemistry, and enantiopharmacology of 3-methyl-AA (4a–d), 4-methyl-AA (5a–d), 5-methyl-AA (6a–d), and (E)-Δ4-5-methyl-AA (7a and 7b) are reported. The compounds were resolved using chiral HPLC and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses, chemical correlation, and CD spectral analyses. The effects of the individual stereoisomers at ionotropic and metabotropic (S)-Glu receptors (iGluRs and mGluRs) were characterized. Compounds with S-configuration at the α-carbon generally showed mGluR2 agonist activity of similar or slightly lower potencies than (S)-AA [e.g., EC50 = 76 μM for (2S,4S)-4-methyl-AA (5a) as compared to EC50 = 35 μM for (S)-AA]. The position of the methyl substituent had a profound effect on the observed pharmacology, whereas the absolute stereochemistry at the methylated carbon atom had a very limited effect on pharmacology. Structure–activity relationships at iGluRs in the rat cortical wedge preparation showed a complex pattern, some compounds being NMDA receptor agonists [e.g., EC50 =110 μM for (2S,5RS)-5-methyl-AA (6a,b)] and some compounds showing NMDA receptor antagonist effects [e.g., IC50 = 300 μM for (2R,4S)-4-methyl-AA (5d)]. The two unsaturated analogs (S)- (7a) and (R)-(E)-Δ4-5-methyl-AA (7b) turned out to be a weak AMPA receptor agonist and a weak mixed NMDA/AMPA receptor antagonist, respectively. Chirality 14:351–363, 2002. © 2002 Wiley-Liss, Inc.

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