Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
(S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic
acid (AMPA) receptors comprise an important class of ionotropic glutamate
receptors activated by glutamate in the central nervous system. These
receptors have been shown to be involved in brain diseases, for example,
Alzheimer’s disease and epilepsy. To understand the functional
role of AMPA receptors at the molecular level and their potential
as targets for drugs, development of tool compounds is essential.
We have previously reported the synthesis of six bicyclic pyrimidinedione-based
analogues of willardiine with differences limited to the pyrimidinedione-fused
five-membered rings. Despite minor molecular differences, we observed
>500-fold difference in binding affinity of the compounds at full-length
GluA2. Here, we report binding affinities and the binding mode of
these compounds at the ligand-binding domain of GluA2 using X-ray
crystallography. The structures revealed similar binding modes, with
distinct differences in the interaction between GluA2 and the compounds.
The methylene (2) and sulfur (3) containing
compounds showed the greatest binding affinities. Changing the dihydrothiophene
(3) into pyrrolidine (4), N-methyl pyrrolidine (5), or dihydrofuran (6) induced flexibility in the position of a binding-site water molecule
and changes in the hydrogen-bonding network between compound, water,
and GluA2. This might be essential for explaining the reduced binding
affinity of these compounds. The weakest binding affinity was observed
when the aliphatic oxygen containing dihydrofuran (6)
was changed into an aromatic furan system (7). Molecular
docking studies revealed two possible orientations of 7, whereas only one binding mode was observed for the other analogues.
This could likely contribute to the weakest binding affinity of 7 at GluA2.
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