119522-93-9Relevant academic research and scientific papers
Heteroaryl analogues of AMPA. 2. Synthesis, absolute stereochemistry, photochemistry, and structure-activity relationships
Falch, Erik,Brehm, Lotte,Mikkelsen, Ivan,Johansen, Tommy N.,Skj?rb?k, Niels,Nielsen, Birgitte,Stensb?l, Tine B.,Ebert, Bjarke,Krogsgaard-Larsen, Povl
, p. 2513 - 2523 (2007/10/03)
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]propionic 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 confirmed by an X-ray crystallographic analysis of 9·HCl. In receptor binding (IC50 values) and rat cortical wedge electrophysiological (EC50 values) studies, 7c (IC50 = 5.5 ± 0.6 μM; EC50 = 96 ± 5 μM) was shown to be markedly weaker than 7a (IC50 = 0.57 ± 0.16 μM; EC50 = 7.4 ± 0.2 μM) as an AMPA agonist, whereas 7b,d,e were inactive. The very potent AMPA agonist effect of 7f (IC50 = 0.15 ± 0.03 μM; EC50 = 1.7 ± 0.2 μM) was shown to reside exclusively in 8 (IC50 = 0.11 ± 0.01 μM; EC50 = 0.71 ± 0.11 μM), whereas 9 did not interact significantly with AMPA receptors, either as an agonist or as an antagonist. 8 was shown to be photochemically active and is a potential photoaffinity label for the recognition site of the AMPA receptors. Compound 7g turned out to be a very weak AMPA receptor agonist (IC50 = 12 ± 0.7 μM; EC50 = 160 ± 15 μM). None of these new compounds showed detectable effects at N-methyl-D-aspartic acid (NMDA) or kainic acid receptors in vitro. The present studies have emphasized that the presence of a heteroatom in the 2-position of the heteroaryl 5-substituent greatly facilitates AMPA receptor agonist activity.
