Heteroaryl analogues of AMPA. 2. Synthesis, absolute stereochemistry, photochemistry, and structure-activity relationships

Journal of Medicinal Chemistry
E FalchP Krogsgaard-Larsen

Abstract

We have previously shown that (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA, 2] is a weak agonist at (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors, specifically activated by (S)-AMPA (1), whereas (S)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-4-isoxazolyl]propionic acid [(S)-2-Py-AMPA, 5] and (RS)-2-amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid (4) are potent AMPA agonists. On the other hand, (R)-APPA (3) and (R)-2-Py-AMPA (6) have been shown to be weak AMPA antagonists. We now report the synthesis of 2-Py-AMPA (7a) and the isomeric compounds 3-Py-AMPA (7b) and 4-Py-AMPA (7c) as well as the 7a analogues, (RS)-2-amino-3-[3-hydroxy-5-(6-methyl-2-pyridyl)-4-isoxazolyl]p ropion ic acid (7d) and (RS)-2-amino-3-[3-hydroxy-5-(2-quinolinyl)-4-isoxazolyl]propionic acid (7e). Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-furyl)-4-isoxazolyl]propionic acid (2-Fu-AMPA, 7f) and its 5-bromo-2-furyl derivative (7g) were synthesized, and (S)-2-Fu-AMPA (8) and (R)-2-Fu-AMPA (9) were prepared by semipreparative chiral HPLC resolution of 7f. HPLC analyses and circular dichroism spectroscopy indicated the absolute stereochemistry of 8 and 9 to be S and R, respectively. This was con...Continue Reading

References

Feb 28, 1985·Neuroscience Letters·T Honoré, M Nielsen
Feb 1, 1985·British Journal of Pharmacology·N L Harrison, M A Simmonds
Sep 1, 1996·Neurochemistry International·B EbertP Krogsgaard-Larsen
Aug 29, 1997·Journal of Medicinal Chemistry·B Bang-AndersenP Krogsgaard-Larsen
Mar 21, 1998·Bioorganic & Medicinal Chemistry·N SkjaerbaekP Krogsgaard-Larsen

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Citations

Oct 8, 1999·European Journal of Pharmacology·T B StensbølP Krogsgaard-Larsen
Jul 16, 2008·Medicinal Research Reviews·Lennart Bunch, Povl Krogsgaard-Larsen
Apr 9, 2004·Organic Letters·David J BurkhartNicholas R Natale
Aug 8, 2006·Medicinal Research Reviews·Daniela CatarziFlavia Varano
Mar 5, 2008·Journal of Neuro-oncology·John F de GrootW K Alfred Yung
Jul 14, 2000·Journal of Medicinal Chemistry·H Bräuner-OsborneP Krogsgaard-Larsen
Feb 14, 2004·The Journal of Organic Chemistry·Birgitte H KaaeTommy N Johansen

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