In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic R-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC.Whereas 12 showed good affinity exclusively atNMDAreceptors, the Glu analogue, (þ)- 10, was an unselective, though potent AMPA receptor preferring agonist (EC50 = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (þ)-15 and (þ)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)- isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

4-Hydroxy-1,2,5-oxadiazol-3-yl Moiety as Bioisoster of the Carboxy Function. Synthesis, Ionization Constants, and Molecular Pharmacological Characterization at Ionotropic Glutamate Receptors of Compounds Related to Glutamate and Its Homologues

LOLLI, Marco Lucio;ROLANDO, Barbara;FOTI, ANTONIO;FRUTTERO, Roberta;GASCO, Alberto;
2010

Abstract

In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic R-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC.Whereas 12 showed good affinity exclusively atNMDAreceptors, the Glu analogue, (þ)- 10, was an unselective, though potent AMPA receptor preferring agonist (EC50 = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (þ)-15 and (þ)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)- isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.
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http://pubs.acs.org/doi/abs/10.1021/jm1001452
1; 2; 5-oxadiazole; bioisoster; bioisosterism; Glutamic acid; AMPA
Marco L. Lolli; Cecilia Giordano; Darryl S. Pickering; Barbara Rolando; Kasper B. Hansen; Antonio Foti; Alberto Contreras-Sanz; Ahmad Amir; Roberta Fruttero; Alberto Gasco; Birgitte Nielsen; Tommy N. Johansen
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/76221
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