Search for Inhibitors of Ionotropic Glutamate Receptors in a Series of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole Derivatives

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In the present work, 14 new diazepinebenzimidazole derivatives (DAB series) were screened for inhibitory activity against NMDA- and Ca2+-impermeable (CI) AMPA-receptors. Experiments were conducted on isolated Wistar rat neurons; pyramidal neurons of the CA1 zone of the hippocampus were used to study NMDA- and CI-AMPA-receptors. Cell isolation was performed by vibrodissociation, and currents were recorded by whole-cell patch-clamp method. All the studied compounds at a concentration of 100 μM inhibited NMDA-receptors (≥30%), while CI-AMPA receptors currents were inhibited by only four compounds: DAB-8, DAB-12, DAB-19, and DAB-32. DAB-8, DAB-12 and DAB-32 have a 4-substituted phenacyl group at the nitrogen atom N11 with an electronegative fluorine atom in the para position (DAB-8 and DAB-32) or without it (DAB-12), whereas the most active compound DAB-19 has a 4-tert-butyl-benzyl group at atom N11 with a bulky tert-butyl substituent in the para position. The most active of them were DAB-12, DAB-19, and DAB-32, which were studied further for their IC50 values. Compound DAB-19 demonstrated the most pronounced activity against both NMDA- and CI-AMPA-receptors: IC50 values were 11,0 ± 1,6 µM and 15,4 ± 1,4 µM, respectively. Such an ability to inhibit both NMDA- and CI-AMPA-receptors at such concentrations is quite remarkable. Based on previous data on the neuropsychotropic effects of DAB-19, we put forward hypothesis about its possible anticonvulsant activity, which was confirmed in the "Pentylenetetrazol Seizure" test. The identification of DAB-19 as a combined antagonist of NMDA- and CI-AMPA-receptors is an important achievement for the further development of effective anticonvulsants.

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M. Dron

Sechenov Institute of Evolutionary Physiology and Biochemistry of the RAS

编辑信件的主要联系方式.
Email: neuro.mike@yahoo.com
俄罗斯联邦, Saint Petersburg

D. Maltsev

Volgograd State Medical University

Email: neuro.mike@yahoo.com
俄罗斯联邦, Volgograd

A. Spasov

Volgograd State Medical University

Email: neuro.mike@yahoo.com
俄罗斯联邦, Volgograd

L. Divaeva

Southern Federal University

Email: neuro.mike@yahoo.com
俄罗斯联邦, Rostov-on-Don

V. Sochnev

Southern Federal University

Email: neuro.mike@yahoo.com
俄罗斯联邦, Rostov-on-Don

A. Morkovnik

Southern Federal University

Email: neuro.mike@yahoo.com
俄罗斯联邦, Rostov-on-Don

O. Barygin

Sechenov Institute of Evolutionary Physiology and Biochemistry of the RAS

Email: neuro.mike@yahoo.com
俄罗斯联邦, Saint Petersburg

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2. Fig. 1. Structural formulae of the investigated N11-substituted derivatives of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole. The compounds were used in the form of hydroiodide (DAB-1), hydrobromides (DAB-7, DAB-8, DAB-12, DAB-19, DAB-32), hydrochlorides (DAB 40, DAB-41), dihydrochlorides (DAB-20, DAB-21, DAB-22).

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3. Fig. 2. Electrophysiological characterisation of the activities of the compounds evaluated in the screening phase: (a) - DAB-8 at a concentration of 100 μM causes inhibition of 50% of the integrin current of NMDA receptors expressed on CA1-zone hippocampal pyramidal neurons; (b) - DAB-40 at a concentration of 100 μM shows marked inhibitory activity against NMDA receptors; (c) - DAB-8 shows inhibitory activity of KN-AMPA-receptors comparable to that of this compound on NMDA-receptors; (d) - DAB-22 is a low-active inhibitor of KN-AMPA-receptors of pyramidal neurons of CA1-zone of hippocampus.

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4. Fig. 3. Electrophysiological description of the action of the most active diazepinobenzimidazole derivatives on NMDA- and KN-AMPA-receptors: (a) - inhibition of NMDA-receptors by the compound DAB-19 at different concentrations; (b) - concentration dependence curves describing the action of DAB-12, DAB-19 and DAB-32 on NMDA-receptors; (c) - concentration dependence of inhibition of KN-AMPA-receptors by the compound DAB-19; (d) - concentration dependence of inhibition of KN-AMPA-receptors by diazepinobenzimidazoles DAB-12, DAB-19 and DAB-32.

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