3'-(Arylmethyl)- and 3'-(Aryloxy)-3-phenyl-4-hydroxyquinolin- 2(1H)-ones: Orally Active Antagonists of the Glycine Site on the NMDA Receptor

Kulagowski, Janusz J.; Baker, Raymond; Curtis, Neil R.; Mawer, Ian M.; Moseley, Angela M.; Ridgill, Mark P.; Rowley, Michael; Stansfield, Ian; Leeson, Paul D.

doi:10.1021/jm00036a002

Cited by 129 publications

(58 citation statements)

References 6 publications

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“…Neither L-687,414 nor L-701,324 had any effect on the volume of the injected (Kemp & Leeson, 1993) and thus it could be argued that the effects of the test compounds in the current study were due to effects on the motor system rather than true antinociceptive effects. However, L-701,324 had significant effects in the current study at doses 10 fold below those which affect motor function (Kulagowski et al, 1994), so the actions of this compound are very likely to be antinociceptive. In contrast, for L-687,414 there was no separation between doses having a significant antinociceptive effect in the current study and those known to affect motor function (Saywell et al, 1991).…”

Section: Discussionmentioning

confidence: 55%

“…Both compounds have been found to be very active as anticonvulsants in mice when administered i.p. (see Table 1), thus indicating good brain penetration (see Kulagowski et al, 1994, for discussion of the relative brain penetration and in vivo activity of these and related compounds). Neither L-687,414 nor L-701,324 had any effect on the volume of the injected (Kemp & Leeson, 1993) and thus it could be argued that the effects of the test compounds in the current study were due to effects on the motor system rather than true antinociceptive effects.…”

Section: Discussionmentioning

confidence: 99%

“…The aims of the study were to examine further the role of the NMDA receptor in mechanical hyperalgesia, and specifically to test the effects of antagonism of the glycine modulatory site on mechanical hyperalgesia. To control for the possibility that any effects seen were due to non-specific actions, two structurally different compounds were used: L-687,414, a partial agonist with lower efficacy and higher affinity at the glycine modulatory site than (+)-HA-966 (Kemp & Leeson, 1993), and L-701,324 (Kulagowski et al, 1994) a structurally novel, high affinity, selective full antagonist for the NMDA/glycine site ( Table 1). Some of these results have been published in abstract form .…”

Section: Introductionmentioning

confidence: 99%

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Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation‐induced mechanical hyperalgesia in rats

Laird

Mason

Webb

et al. 1996

British J Pharmacology

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation‐induced mechanical hyperalgesia in rats

Laird

Mason

Webb

et al. 1996

British J Pharmacology

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“…Thus, within these families, development of larger antagonists that probe the S1/S2 cleft may yield high-affinity antagonists. For the glycine-binding site of NR1, the bulky compound L-701,324 (Kulagowski et al, 1994) may represent such an antagonist. At the same time, it might be expected that large antagonists with side groups that reach the subunit-specific regions of the S1/S2 cleft could have modified subtype selectivity.…”

Section: Discussionmentioning

confidence: 99%

Identification of Subunit- and Antagonist-Specific Amino Acid Residues in theN-Methyl-d-aspartate Receptor Glutamate-Binding Pocket

Kinarsky

Feng

Skifter

et al. 2005

J Pharmacol Exp Ther

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The resolved X-ray crystal structures of the glutamate-binding domain (S1/S2 domains) of the GluR2 and NR1 glutamate receptor subunits were used to model the homologous regions of the N-methyl-D-aspartate (NMDA) receptor's NR2 subunits. To test the predictive value of these models, all four stereoisomers of the antagonist 1-(phenanthren-2-carbonyl) piperazine-2,3-dicarboxylic acid (PPDA) were docked into the NR2B glutamate-binding site model. This analysis suggested an affinity order for the PPDA isomers of D-cis Ͼ L-cis Ͼ L-trans ϭ D-trans and predicted that the 2-position carboxylate group of the cis-PPDA isomers, but not of the trans-PPDA isomers, may be interacting with histidine 486 in NR2B. Consistent with these predictions, cis-PPDA displays a 35-fold higher affinity for NR2B-containing NMDA receptors than trans-PPDA. In addition, mutating NR2B's H486 to phenylalanine decreased cis-PPDA affinity 8-fold but had no effect on trans-PPDA affinity. In contrast, the NR2B H486F mutation increased the affinity of the typical antagonists CGS-19755 [(2R*,4S*)-4-phosphonomethyl-2-piperidine carboxylic acid] and 4-(3-phosphonopropyl) piperidine-2-carboxylic acid. In the NR1-based NR2 models, there were only four subunit-specific amino acid residues exposed to the ligand-binding pocket (and six in the GluR2-based models). These residues are located at the edge of the binding pocket, suggesting that large antagonists may be necessary for subtype specificity. Of these residues, mutational analysis and modeling suggest that A414, R712, and G713 (NR2B numbering) may be especially useful for developing NR2C-and NR2D-selective NMDA receptor antagonists and that residues A414 and T428 may determine subunit variations in agonist affinity.

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“…In this paper, we describe the synthesis and properties of twelve reactive analogues of L-698.532 (1), L-701.324 (2), 20 and its 4-amino derivative (3) 22 (Chart 1). Their binding to rat brain membrane NMDA receptor of the wild-type is reported and discussed in terms of structure-activity relationships; their affinity is correlated to their antagonistic activity against glutamate/ glycine-induced currents in oocytes expressing the NR1 A /NR2B combination of receptor subunits.…”

Section: Introductionmentioning

confidence: 99%

Evaluation and Biological Properties of Reactive Ligands for the Mapping of the Glycine Site on theN-Methyl-d-aspartate (NMDA) Receptor

et al. 1999

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The glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, given its potential as pharmacological target, has been thoroughly studied by structure-activity relationships, which has made possible its description in terms of spatial limits and interactions of various types. A structural model, based on mutational analysis and sequence alignements, has been proposed. Yet, the amino acid residues responsible for the interactions with the ligand have not been unambiguously characterized. To evidence nucleophilic pocket-lining residues, we have designed and synthesized reactive glycine-site ligands derived from 3-substituted 4-hydroxy-quinolin-2(1H)-ones by introducing various electrophilic groups at different positions of the molecule. These ligands were found to have high affinity at the glycine site and to be functional antagonists by inhibiting glycine/glutamate-induced currents in transfected oocytes. The correlation between their potency and their substitution pattern was strictly consistent with previously established structure-activity relationships. Most ligands displayed intrinsic reactivity toward cysteine, but none inactivated wild-type receptors. This is consistent with the model since it indicates the absence of exposed cysteine in the glycine-binding site. A strategy of cysteine incorporation by point mutations at selected polypeptide positions will create unambiguously localized targets for our reactive probes.

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3'-(Arylmethyl)- and 3'-(Aryloxy)-3-phenyl-4-hydroxyquinolin- 2(1H)-ones: Orally Active Antagonists of the Glycine Site on the NMDA Receptor

Cited by 129 publications

References 6 publications

Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation‐induced mechanical hyperalgesia in rats

Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation‐induced mechanical hyperalgesia in rats

Identification of Subunit- and Antagonist-Specific Amino Acid Residues in theN-Methyl-d-aspartate Receptor Glutamate-Binding Pocket

Evaluation and Biological Properties of Reactive Ligands for the Mapping of the Glycine Site on theN-Methyl-d-aspartate (NMDA) Receptor

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