L-(+)-2-Amino-4-thiophosphonobutyric Acid (L-thioAP4), a New Potent Agonist of Group III Metabotropic Glutamate Receptors: Increased Distal Acidity Affords Enhanced Potency

Chelliah Selvam, Cyril Goudet, Nadia Oueslati, Jean-Philippe Pin, Francine C Acher

J Med Chem. 2007 Sep 20;50(19):4656-64.

PMID: 17722902

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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Catalog Number	Product Name	Structure	CAS Number	Price
AP20263074	(±)-2-Amino-4-phosphonobutyric acid		20263-07-4	Price
AP23052815-A	L-(+)-2-Amino-4-phosphonobutyric acid		23052-81-5	Price