title: Synthesis and pharmacological evaluation of novel conformationally constrained homologues of glutamic acid.
abstract: Twelve novel conformationally constrained homologues of glutamic acid have been synthesized and pharmacologically characterized at ionotropic glutamate receptors (iGluRs). Synthesis of the target compounds involved 1,3-dipolar cycloaddition of nitrile oxides to suitable dipolarophiles. The structure to the compounds has been assigned by (1)H NMR and, in the case of derivatives (+/-)-4a, (+/-)-4b, (+/-)-5a, and (+/-)-5b, by means of an X-ray crystallographic analysis carried out on intermediate (+/-)-12a. The synthesized amino acids were found to be without affinity (K(i)/IC(50)>100microM) for iGluRs with the exception of compounds (+/-)-4b and (+/-)-5b, which showed a modest affinity for NMDA receptors (K(i)=34 and 13microM, respectively). The results indicate that the increased conformational constraints introduced by the cyclopropane ring and the spiro-attached proline ring are both detrimental to the pharmacological activity.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Antonio
authors.initials: A
authors.lastname: Caligiuri
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Gabriella
authors.initials: G
authors.lastname: Roda
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Alessio
authors.initials: A
authors.lastname: Colombo
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011485:Protein Binding; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid