title: Identification of a novel structural class of positive modulators of the N-methyl-D-aspartate receptor, with actions mediated through the glycine recognition site.
abstract: This study describes a new structural class of compounds which interact at the N-methyl-D-aspartate (NMDA) receptor-associated glycine recognition site. These E-gamma-substituted vinylglycine derivatives were active in displacing [3H]glycine binding from the NMDA receptor-associated recognition site in rat forebrain synaptic plasma membranes, with Ki values in the range of 0.24-8.7 microM. Functional analyses of these compounds indicate that they positively modulate basal [3H](+)-5-methyl-10,11-dihydro-5H- [a,d]cyclohepaten-5,10-imine ([3H]MK-801) binding, consistent with their having agonist characteristics. Little stereospecificity is observed with the gamma-substituted methyl and propyl derivatives while the L-isomer of the hexyl analog is significantly more potent than the D-isomer. The D- and L-hydroxyethyl gamma-substituted vinylglycines were the most potent inhibitors of [3H]glycine binding with Ki values of 0.75 +/- 0.06 microM and 0.24 +/- 0.02 microM, respectively. The 3,4-double bond was necessary for activity in that the saturated hexyl derivative (2-aminodecanoate) was inactive. Based on the results reported herein, the hypothesis that there is a distinct size restriction for functional agonists which interact with the glycine recognition site, should be altered to include these larger extensions of vinylglycine.
authors.affiliation: Searle Research and Development, Division of G.D. Searle & Co., St. Louis, MO 63198.
authors.forename: J B
authors.initials: JB
authors.lastname: Monahan
authors.forename: W F
authors.initials: WF
authors.lastname: Hood
authors.forename: R P
authors.initials: RP
authors.lastname: Compton
authors.forename: A A
authors.initials: AA
authors.lastname: Cordi
authors.forename: R M
authors.initials: RM
authors.lastname: Williams
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis; D066298:In Vitro Techniques; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000596:Amino Acids; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C006507:vinylglycine; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine