Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 51, Issue 7, Pages 1573-1582Publisher
WILEY
DOI: 10.1111/ejn.14589
Keywords
diminazene; glutamate receptors; patch clamp; pentamidine; pharmacological modulation
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Funding
- Russian Science Foundation [17-74-10117]
- Ministry of Science and Higher Education, Russia
- Russian Science Foundation [17-74-10117] Funding Source: Russian Science Foundation
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Pentamidine, diminazene and 4 ',6-diamidino-2-phenylindole (DAPI) are antiprotozoal diarylamidine compounds. In the present work, we have studied their action on native N-methyl-D-aspartate (NMDA) receptors in rat hippocampal pyramidal neurons. All three compounds inhibited NMDA receptors at -80 mV holding voltage with IC50 of 0.41 +/- 0.08, 13 +/- 3 and 3.1 +/- 0.6 mu M, respectively. The inhibition by pentamidine was strongly voltage-dependent, while that of DAPI was practically voltage-independent. Inhibition by diminazene had both voltage-dependent and voltage-independent components. Diminazene and DAPI demonstrated tail currents and overshoots suggesting foot-in-the-door mechanism of action. In contrast, pentamidine was partially trapped in the closed NMDA receptor channels. Such difference in the mechanism of action can be explained by the difference in the 3D structure of compounds. In the pentamidine molecule, two benzamidine groups are connected with a flexible linker, which allows the molecule to fold up and fit in the cavity of a closed NMDA receptor channel. Diminazene and DAPI, in contrast, have an extended form and could not be trapped.
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