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 μM, respectively) in comparison to L-AP4 (EC50 = 0.08 μM), whereas L-thioAP4 has a 2-fold higher potency (EC50 = 0.039 μM). 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 pK a 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. © 2007 American Chemical Society.