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L-(+)-2-Amino-4-thiophosphonobutyric acid (L-thioAP4), a new potent agonist of group III metabotropic glutamate receptors: increased distal acidity affords enhanced potency.

Abstract : L-2-Amino-4-phosphonobutyric acid (l-AP4), l-2-amino-4-thiophosphonobutyric acid (l-thioAP4), and l-2-amino-4-(hydroxy)phosphinylbutyric acid (desmethylphosphinothricin, DMPT) were synthesized from protected vinylglycine. They were tested as agonists at group III metabotropic glutamate receptors (mGluR) along with phosphinothricin (PT). DMPT and PT display a much lower potency at mGlu4 receptor (EC50 = 4.0 and 1100 microM, respectively) in comparison to l-AP4 (EC50 = 0.08 microM), whereas l-thioAP4 has a 2-fold higher potency (EC50 = 0.039 microM). Similar rank orders of potency were observed at mGlu6,7 and mGlu8 receptors. The higher potency of l-thioAP4 is due to its stronger second acidity compared to l-AP4. These pKa values of 5.56 and 6.88, respectively, were determined using 31P NMR chemical shift variations. The second distal negative charge of l-AP4/l-thioAP4 probably provides stronger binding to specific basic residues of the binding sites of group III mGluRs, which stabilizes the active conformation of the receptor.
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https://www.hal.inserm.fr/inserm-00318965
Contributor : Cyril Goudet <>
Submitted on : Friday, September 5, 2008 - 11:44:04 AM
Last modification on : Thursday, September 24, 2020 - 5:58:41 PM
Long-term archiving on: : Saturday, November 26, 2016 - 12:44:57 AM

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Chelliah Selvam, Cyril Goudet, Nadia Oueslati, Jean-Philippe Pin, Francine Acher. L-(+)-2-Amino-4-thiophosphonobutyric acid (L-thioAP4), a new potent agonist of group III metabotropic glutamate receptors: increased distal acidity affords enhanced potency.. Journal of Medicinal Chemistry, American Chemical Society, 2007, 50 (19), pp.4656-64. ⟨10.1021/jm070400y⟩. ⟨inserm-00318965⟩

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