title: Synthesis and biological evaluation of cyclopropyl analogues of 2-amino-5-phosphonopentanoic acid.
abstract: A series of cyclopropyl analogues related to 2-amino-5-phosphonopentanoic acid (AP5) were synthesized and their biological activity was assessed as competitive antagonists for the N-methyl-D-aspartate (NMDA) receptor. In vitro receptor binding using [3H]-L-glutamate as the radioligand provided affinity data, while modulation of [3H]MK-801 binding was used as a functional assay. The analogues were also evaluated in [3H]kainate binding to assess selectivity over non-NMDA glutamate receptors. Of the compounds tested, 4,5-methano-AP5 analogue 26 was the most potent selective NMDA antagonist; however, potency was lower than that for [[(+/-)-2-carboxypiperidin-4-yl]methyl]phosphonic acid (CGS 19755, 5).
authors.affiliation: Searle Research and Development, Skokie, Illinois 60077.
authors.forename: M S
authors.initials: MS
authors.lastname: Dappen
authors.forename: R
authors.initials: R
authors.lastname: Pellicciari
authors.forename: B
authors.initials: B
authors.lastname: Natalini
authors.forename: J B
authors.initials: JB
authors.lastname: Monahan
authors.forename: C
authors.initials: C
authors.lastname: Chiorri
authors.forename: A A
authors.initials: AA
authors.lastname: Cordi
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D007202:Indicators and Reagents; D007608:Kainic Acid / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism*; D014316:Tritium
chemical_list: D005971:Glutamates; D007202:Indicators and Reagents; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D007608:Kainic Acid