Synthesis and biological evaluation of 1-amino-2-phosphonomethylcyclopropanecarboxylic acids, new group III metabotropic glutamate receptor agonists.
Stereoisomers of 1-amino-2-phosphonomethylcyclopropanecarboxylic acid (APCPr), conformationally restricted analogues of L-AP4 (2-amino-4-phosphonobutyric acid), have been prepared and evaluated at recombinant group III metabotropic glutamate receptors. They activate these receptors over a broad range of potencies. The most potent isomer (1S,2R)-APCPr displays a similar pharmacological profile as that of L-AP4 (EC50 0.72, 1.95, >500, 0.34 microM at mGlu4, 6, 7, 8 receptors, respectively, and no effect at group I/II mGluRs). It was characterized on native receptors located in the basal ganglia (BG) where it induced a robust and reversible inhibition of synaptic transmission. It was tested in vivo in haloperidol-induced catalepsy, a model of Parkinsonian akinesia, by direct infusion in the globus pallidus of the BG. At a dose of 0.5 nmol/microL, catalepsy was significantly antagonized. This study reveals that (1S,2R)-APCPr is a potent group III mGluR agonist and confirms that these receptors may be considered as a therapeutic target in the Parkinson's disease.
Sibille
Pauline
P
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, CNRS UMR-8601, University Paris Descartes, 45 rue des Saints Péres, 75270 Paris Cedex 06, France.
Lopez
Sébastien
S
Brabet
Isabelle
I
Valenti
Ornella
O
Oueslati
Nadia
N
Gaven
Florence
F
Goudet
Cyril
C
Bertrand
Hugues-Olivier
HO
Neyton
Jacques
J
Marino
Michael J
MJ
Amalric
Marianne
M
Pin
Jean-Philippe
JP
Acher
Francine C
FC
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects / Q000502:physiology; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D002460:Cell Line; D006220:Haloperidol; D006801:Humans; D066298:In Vitro Techniques; D007267:Injections; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
C523415:1-amino-2-phosphonomethylcyclopropanecarboxylic acid; D000596:Amino Acids; D000978:Antiparkinson Agents; D063065:Organophosphonates; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D006220:Haloperidol