title: Subtype-selective antagonism of NMDA receptors by nylidrin.
abstract: The 1,4-di-substituted piperidines ifenprodil, eliprodil, CP 101,606 ((1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol ) and Ro 25-6981 ((R-(R*,S*))-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenyl-methyl)-1- piperidinepropanol) are allosteric antagonists of NMDA receptors. Inhibition of diheteromeric NMDA receptors by this class of antagonist is characterized by pronounced selectivity for NR1/2B subunit combinations. In the current study, we assayed effects of nylidrin, a structurally-related non-piperidine, on recombinant and neuronal NMDA receptors. Nylidrin was a potent (IC50 = 0.18 microM) antagonist of NR1A/2B receptors expressed in Xenopus oocytes and was at least 150-fold weaker against NR1A/2A and NR1A/2C receptors. The blockade of NR1A/2B responses by nylidrin was not surmounted by increasing the concentrations of glutamate or glycine and was not voltage-dependent. Potency of inhibition increased approximately 3-fold upon lowering extracellular pH from 8 to 6.8. Nylidrin inhibited NMDA responses in cultured rat cortical neurons with similar potency and apparent mechanism of action as the NR1A/2B receptors. Our results suggest that nylidrin interacts with the same allosteric inhibitory site previously described for the related piperidine antagonists, and should serve as a structural lead for designing novel subtype-selective inhibitors of NMDA receptors.
authors.affiliation: CoCensys Inc., Irvine, CA 92618, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: V I
authors.initials: VI
authors.lastname: Ilyin
authors.forename: C S
authors.initials: CS
authors.lastname: Konkoy
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009756:Nylidrin / Q000494:pharmacology*; D009865:Oocytes; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014981:Xenopus
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D009756:Nylidrin