title: Synthesis and studies on the mGluR agonist activity of FAP4 stereoisomers.
abstract: The four stereoisomers of 1-amino-2-fluoro-2-(phosphonomethyl)cyclopropane-1-carboxylic acid (FAP4) were synthesized via diastereoselective Rh(II)-catalysed cyclopropanation of a phosphonylated fluoroalkene. Different isomers of FAP4 and the corresponding non-fluorinated analogs showed a similar pharmacological profile against the isoforms of metabotropic glutamate receptor (mGluR). Within the fluorinated series, (-)-(Z)-FAP4 and (-)-(E)-FAP4 demonstrated the highest agonist activity against mGlu4 (EC50 0.10 μM). Our results suggest that fluorocyclopropanes bearing an amino-acid function can be suitable for the development of potent conformationally restricted mGluR agonists.
authors.affiliation: NormandieUniv., COBRA, UMR 6014 & FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Pavel
authors.initials: P
authors.lastname: Ivashkin
authors.affiliation: NormandieUniv., COBRA, UMR 6014 & FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Lemonnier
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR5203, Université de Montpellier, F-34094 Montpellier, France; INSERM U1191, F-34094 Montpellier, France.
authors.forename: Amélie S
authors.initials: AS
authors.lastname: Tora
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR5203, Université de Montpellier, F-34094 Montpellier, France; INSERM U1191, F-34094 Montpellier, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR5203, Université de Montpellier, F-34094 Montpellier, France; INSERM U1191, F-34094 Montpellier, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
authors.affiliation: NormandieUniv., COBRA, UMR 6014 & FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France. Electronic address: philippe.jubault@insa-rouen.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jubault
authors.affiliation: NormandieUniv., COBRA, UMR 6014 & FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pannecoucke
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D003521:Cyclopropanes / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D002264:Carboxylic Acids; D003521:Cyclopropanes; D020033:Protein Isoforms; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; C030797:cyclopropane
keywords: Amino-acids; Cyclopropane; Fluorine; Metabotropic glutamate receptor; Phosphonic acid