L-(+)-2-Amino-4-thiophosphonobutyric acid (L-thioAP4), a new potent agonist of group III metabotropic glutamate receptors: increased distal acidity affords enhanced potency.
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.
Selvam
Chelliah
C
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR-8601, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Goudet
Cyril
C
Oueslati
Nadia
N
Pin
Jean-Philippe
JP
Acher
Francine C
FC
D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C523627:2-amino-4-thiophosphonobutyric acid; D000613:Aminobutyrates; D007295:Inositol Phosphates; D009946:Organothiophosphorus Compounds; D010721:Phosphinic Acids; D018094:Receptors, Metabotropic Glutamate; C523626:desmethylphosphinothricin; C012729:2-amino-4-phosphonobutyric acid