title: Synthesis and pharmacological evaluation of conformationally constrained glutamic acid higher homologues.
abstract: Homologation of glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. In the present work, starting from two potent and selective unnatural amino acids previously developed by us, we investigated the effects on the activity/selectivity profile produced by a further increase in the distance between the amino acidic moiety and the distal carboxylate group. Interestingly, the insertion of an aromatic ring as a spacer produced a low micromolar affinity NMDA ligand that might represent a lead for the development of a new class of NMDA antagonists.
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Cullia
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen OE, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy. Electronic address: andrea.pinto@unimi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid
keywords: 1,3-Dipolar cycloaddition; Amino acid; N-Methyl-d-aspartate receptor; l-Glutamic acid; Δ(2)-Isoxazoline