Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro

Boireau, A.; Malgouris, C.; Burgevin, Marie-Claude; Pény, Colette; Durand, G.; Bordier, Françoise; Meunier, Mireille; Miquet, Jean Marie; Daniel, Marc; Chevet, Thierry; Jimonet, Patrick; Mignani, Serge; Blanchard, Jean‐Charles; Doble, Adam

doi:10.1016/0014-2999(95)00780-6

Cited by 14 publications

(3 citation statements)

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“…Preparation and pharmacological evaluation of the parent compound ( 6a ) demonstrated encouraging antagonist activity (IC 50 = 350 nM) at the glycine-NMDA binding site . Introduction of a chloro substituent at position C-8 increased affinity greater than 10-fold ( 6b , IC 50 = 25 nM), an observation well- correlated with the increased affinity observed previously in other heterocyclic families upon related chloro substitutions . Unfortunately, when examined in our primary in vivo screen, the maximum electroshock-induced seizure (MES) test in mice, compound 6b showed very low activity (ED 50 > 80 mg/kg ip).…”

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confidence: 55%

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Indeno[1,2-b]pyrazin-2,3-diones: A New Class of Antagonists at the Glycine Site of the NMDA Receptor with Potent in Vivo Activity

Jimonet¹,

Ribeill²,

Böhme³

et al. 2000

J. Med. Chem.

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Indeno¿1,2-bpyrazin-2,3-diones have been identified as a novel series of potent ligands on the glycine site of the NMDA receptor. To improve their in vivo activities, an acetic acid-type side chain was introduced to the 5-position, giving water-soluble compounds when formulated as the sodium salt (>10 mg/mL). Introduction of a chlorine atom in the 8-position led to a dramatic improvement of anticonvulsant activity and this was surprising since this change did not improve binding affinity. A plausible explanation is a reduced recognition by a Na(+),K(+)-ATPase active transport system responsible for the excretion of these compounds from the brain and kidney. This promising new chemical series led to the optically active isomer (-)-10i (RPR 118723), a glycine/NMDA antagonist with nanomolar binding affinity and in vivo activity in animal model of convulsions and electrophysiology at doses in the range of 2-3 mg/kg following iv administration.

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confidence: 55%

“…Following our previous identification of the benzothiadiazine RPR 104632 ( 4 ) as a potent glycine/NMDA antagonist in vitro but with limited in vivo activity, research was focused on novel chemical families, particularly on the indeno[1,2- b ]pyrazin-2,3-diones such as 6a and 6b (Figure ) . Our initial design was driven by two concepts.…”

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confidence: 99%

Indeno[1,2-b]pyrazin-2,3-diones: A New Class of Antagonists at the Glycine Site of the NMDA Receptor with Potent in Vivo Activity

Jimonet¹,

Ribeill²,

Böhme³

et al. 2000

J. Med. Chem.

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“…N-methyl-D-aspartate (NMDA) receptors have a dichotomous nature, being both pivotal to synaptic plasticity [ 1 ] and a significant mediator of neurotoxicity following acute brain injury, such as strokes [ 2 , 3 ]. NMDAR antagonists are shown to be neuroprotective in multiple ischemia studies in vivo [ 4 , 5 ] and in vitro [ 6 , 7 ], however, their unfavorable toxicity profiles [ 8 ] render their use for clinical therapy challenging. Disruption of the physiological functions of NMDA receptors by such NMDA antagonists may contribute to the side effects that outweigh their neuroprotective benefits [ 9 , 10 ].…”

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confidence: 99%

Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors

et al. 2022

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In this study, we characterize biophysical changes in NMDA receptor function in response to brief non-injurious ischemic stress (ischemic preconditioning). Electrophysiological studies show NMDA receptor function is reduced following preconditioning in cultured rat cortical neurons. This functional change is not due to changes in the reversal potential of the receptor, but an increase in desensitization. We performed concentration–response analysis of NMDA-evoked currents, and demonstrate that preconditioned neurons show a reduced potency of NMDA to evoke currents, an increase in Mg2+ sensitivity, but no change in glycine sensitivity. Antagonists studies show a reduced inhibition of GluN2B antagonists that have an allosteric mode of action (ifenprodil and R-25-6981), but competitive antagonists at the GluR2A and 2B receptor (NVP-AMM077 and conantokin-G) appear to have similar potency to block currents. Biochemical studies show a reduction in membrane surface GluN2B subunits, and an increased co-immunoprecipitation of GluN2A with GluN2B subunits, suggestive of tri-heteromeric receptor formation. Finally, we show that blocking actin remodeling with jasplakinolide, a mechanism of rapid ischemic tolerance, prevents NMDA receptor functional changes and co-immunoprecipitation of GluN2A and 2B subunits. Together, this study shows that alterations in NMDA receptor function following preconditioning ischemia are associated with neuroprotection in rapid ischemic tolerance.

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Functional NMDA Antagonists

Trullás¹

1997

Antidepressants

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Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro

Cited by 14 publications

References 14 publications

Indeno[1,2-b]pyrazin-2,3-diones: A New Class of Antagonists at the Glycine Site of the NMDA Receptor with Potent in Vivo Activity

Indeno[1,2-b]pyrazin-2,3-diones: A New Class of Antagonists at the Glycine Site of the NMDA Receptor with Potent in Vivo Activity

Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors

Functional NMDA Antagonists

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