title: Synthesis and biological evaluation of 1-amino-2-phosphonomethylcyclopropanecarboxylic acids, new group III metabotropic glutamate receptor agonists.
abstract: 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.
authors.affiliation: 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.
authors.forename: Pauline
authors.initials: P
authors.lastname: Sibille
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lopez
authors.forename: Isabelle
authors.initials: I
authors.lastname: Brabet
authors.forename: Ornella
authors.initials: O
authors.lastname: Valenti
authors.forename: Nadia
authors.initials: N
authors.lastname: Oueslati
authors.forename: Florence
authors.initials: F
authors.lastname: Gaven
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
authors.forename: Hugues-Olivier
authors.initials: HO
authors.lastname: Bertrand
authors.forename: Jacques
authors.initials: J
authors.lastname: Neyton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marino
authors.forename: Marianne
authors.initials: M
authors.lastname: Amalric
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.forename: Francine C
authors.initials: FC
authors.lastname: Acher
mesh_terms: 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
chemical_list: 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