Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity

Karlov, Dmitry S.; Temnyakova, Nadezhda S.; Vasilenko, Dmitry A.; Barygin, Oleg I.; Dron, Mikhail Y.; Zhigulin, Arseniy S.; Averina, Elena B.; Grishin, Yu. K.; Grigoriev, V. V.; Gabrel’yan, A. V.; Aniol, V. A.; Gulyaeva, N. V.; Osipenko, Sergey; Kostyukevich, Yury; Palyulin, V. A.; Popov, Petr; Fedorov, Maxim V.

doi:10.1039/d2md00001f

Cited by 3 publications

(2 citation statements)

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“…NMDA receptors of CA1 pyramidal cells contain mainly GluN2A and/or GluN2B subunits in addition to GluN1 [27]. The presence of both GluN2B-containing and GluN2B-lacking NMDA receptors in CA1 pyramidal cells was also confirmed by us previously in experiments with the NR2B-selective antagonist ifenprodil [28]. Indeed, the concentration dependence for ifenprodil was clearly biphasic, with the high-affinity component corresponding to inhibition of GluN2B-containing NMDA receptors and the lowaffinity component corresponding to inhibition of GluN2B-lacking receptors.…”

Section: Discussionsupporting

confidence: 76%

Mechanisms of NMDA Receptor Inhibition by Sepimostat—Comparison with Nafamostat and Diarylamidine Compounds

Zhigulin,

Barygin

2023

IJMS

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N-methyl-D-aspartate (NMDA) receptors are inhibited by many amidine and guanidine compounds. In this work, we studied the mechanisms of their inhibition by sepimostat—an amidine-containing serine protease inhibitor with neuroprotective properties. Sepimostat inhibited native NMDA receptors in rat hippocampal CA1 pyramidal neurons with IC50 of 3.5 ± 0.3 µM at −80 mV holding voltage. It demonstrated complex voltage dependence with voltage-independent and voltage-dependent components, suggesting the presence of shallow and deep binding sites. At −80 mV holding voltage, the voltage-dependent component dominates, and we observed pronounced tail currents and overshoots evidencing a “foot-in-the-door” open channel block. At depolarized voltages, the voltage-independent inhibition by sepimostat was significantly attenuated by the increase of agonist concentration. However, the voltage-independent inhibition was non-competitive. We further compared the mechanisms of the action of sepimostat with those of structurally-related amidine and guanidine compounds—nafamostat, gabexate, furamidine, pentamidine, diminazene, and DAPI—investigated previously. The action of all these compounds can be described by the two-component mechanism. All compounds demonstrated similar affinity to the shallow site, which is responsible for the voltage-independent inhibition, with binding constants in the range of 3–30 µM. In contrast, affinities to the deep site differed dramatically, with nafamostat, furamidine, and pentamidine being much more active.

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Section: Discussionsupporting

confidence: 76%

Mechanisms of NMDA Receptor Inhibition by Sepimostat—Comparison with Nafamostat and Diarylamidine Compounds

Zhigulin,

Barygin

2023

IJMS

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“…Biphenyl-based NMDA negative allosteric modulator (NAM) has low affinity for the human ether-ago-go-related gene ion channel (hERG) and the dynamics calculations suggest a various binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101204 …”

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confidence: 99%

A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects

et al. 2023

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Persulfate-promoted synthesis of biphenyl compounds in water from biomass-derived triacetic acid lactone

Ortin

Salles

2022

Org. Biomol. Chem.

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Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity

Abstract: The activity of biphenyl-based NMDA receptor allosteric modulator identified in virtual screening (IC50 = 5 μM) was improved 100 times (IC50 = 50 nM); SAR is consistent with ifenprodil analogs.

Cited by 3 publications

References 36 publications

Mechanisms of NMDA Receptor Inhibition by Sepimostat—Comparison with Nafamostat and Diarylamidine Compounds

Mechanisms of NMDA Receptor Inhibition by Sepimostat—Comparison with Nafamostat and Diarylamidine Compounds

A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects

Persulfate-promoted synthesis of biphenyl compounds in water from biomass-derived triacetic acid lactone

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