title: Exploration of N-phosphonoalkyl-, N-phosphonoalkenyl-, and N-(phosphonoalkyl)phenyl-spaced alpha-amino acids as competitive N-methyl-D-aspartic acid antagonists.
abstract: A series of N-substituted alpha-amino acids containing terminal phosphonic acid groups has been synthesized as potential N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptor affinity was determined by displacement of a known ligand ([3H]CPP) from crude rat brain synaptic membranes; an antagonist action was demonstrated by the inhibition of glutamate-induced accumulation of [45Ca2+] in cultured rat cortical neurons. Receptor affinity was significantly correlated with antagonist activity (Figure 1). Moderate affinity (IC50 = 1-2 microM) was retained for analogues (31 and 32, Table I; and 59 and 66, Table II) with reduced flexibility in their phosphonate side chains and is consistent with entropy playing a role in determining receptor affinity. Modeling studies suggest a folded conformation that brings the distal phosphonic acid group into close proximity with the alpha-carboxylate is required for binding. Each of the active analogues possess entropy-limiting features (double bonds, phenyl rings) in their side chains that allows the superposition of their key NH2, alpha-COOH, and distal PO3H2 groups with those of known competitive antagonists. Affinity decreased for analogues with alpha-carbon substitution, presumably because the alpha-substituent inhibits the folding of these structures into a bioactive conformation and occupies receptor-excluded volume. A complete description of the NMDA antagonist pharmacophore model is provided in a companion paper.
authors.affiliation: Department of Chemistry and Neuroscience Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: C F
authors.initials: CF
authors.lastname: Bigge
authors.forename: G
authors.initials: G
authors.lastname: Johnson
authors.forename: D F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: J T
authors.initials: JT
authors.lastname: Drummond
authors.forename: D M
authors.initials: DM
authors.lastname: Retz
authors.forename: L J
authors.initials: LJ
authors.lastname: Brahce
authors.forename: L L
authors.initials: LL
authors.lastname: Coughenour
authors.forename: F W
authors.initials: FW
authors.lastname: Marcoux
authors.forename: A W
authors.initials: AW
authors.lastname: Probert
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D008958:Models, Molecular; D008968:Molecular Conformation; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D063065:Organophosphonates; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate