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1.
Brain Res ; 1660: 58-66, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28167075

ABSTRACT

It is known that some antidepressants and antipsychotics directly inhibit NMDA-type ionotropic glutamate receptors. In this study we systematically studied action of seven drugs (Fluoxetine, Citalopram, Desipramine, Amitriptyline, Atomoxetine, Chlorpromazine, and Clozapine) on NMDA receptors and Ca2+-permeable and -impermeable AMPA receptors in rat brain neurons by whole-cell patch-clamp technique. Except for weak effect of fluoxetine, all drugs were virtually inactive against Ca2+-impermeable AMPA receptors. Fluoxetine and desipramine significantly inhibited Ca2+-permeable AMPA receptors (IC50=43±7 and 105±12µM, respectively). Desipramine, atomoxetine and chlorpromazine inhibited NMDA receptors in clinically relevant low micromolar concentrations, while citalopram had only weak effect. All tested medicines have been clustered into two groups by their action on NMDA receptors: desipramine, amitriptyline, chlorpromazine, and atomoxetine display voltage- and magnesium-dependent open channel blocking mechanism. Action of fluoxetine and clozapine was found to be voltage- and magnesium-independent. All voltage-dependent compounds could be trapped in closed NMDA receptor channels. Possible contribution of NMDA receptor inhibition by certain antidepressants and antipsychotics to their analgesic effects in neuropathic pain is discussed.


Subject(s)
Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Brain/drug effects , Neurons/drug effects , Receptors, AMPA/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Amitriptyline/pharmacology , Animals , Atomoxetine Hydrochloride/pharmacology , Brain/metabolism , Chlorpromazine/pharmacology , Citalopram/pharmacology , Desipramine/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Fluoxetine/pharmacology , Magnesium/metabolism , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , N-Methylaspartate/pharmacology , Neurons/metabolism , Neurotransmitter Agents/pharmacology , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/metabolism
2.
Neurosci Lett ; 632: 136-40, 2016 Oct 06.
Article in English | MEDLINE | ID: mdl-27574729

ABSTRACT

Although acid-sensitive ion channels (ASICs) play an important role in brain functions, the exact mechanism of their physiological activation remain unclear. A possible answer to the intriguing question is that some presently unknown endogenous ligand(s) positively modulate ASICs and enhance their responses to physiologically significant level. In the present work we found that histamine selectively potentiates ASIC1a homomers in CHO cells. Action of histamine was particularly pronounced at modest acidifications, which cause minor response. At these conditions micromolar concentrations of histamine have provided significant potentiation of ASIC1a response. We proposed that histamine and possibly some other endogenous amines can positively modulate ASICs functions.


Subject(s)
Acid Sensing Ion Channels/metabolism , Histamine/pharmacology , Ovary/drug effects , Animals , CHO Cells , Cricetulus , Female , Ovary/cytology , Ovary/metabolism , Patch-Clamp Techniques
3.
Eur J Pharmacol ; 788: 75-83, 2016 Oct 05.
Article in English | MEDLINE | ID: mdl-27288880

ABSTRACT

Acid-sensing ion channels (ASICs) are involved in numerous physiological and pathological processes in the central nervous system. Development of pharmacological tools capable to inhibit or potentiate these channels is important for our knowledge about roles of ASICs in the neuronal network and can be promising for treatment of some disorders. Recently we described four hydrophobic monoamines that potentiate and inhibit ASICs depending on subunit composition of the channel and peculiarities of the drug structure. In the present work we performed structure-activity relationship analysis using derivatives of adamantane, phenylcyclohexyl and 9-aminoacridine to reveal the main determinants of action of amine-containing compounds on recombinant ASIC1a and ASIC2a homomers expressed in CHO cells. We found that the most active compounds are monocations with protonatable aminogroup. In general, potentiators and inhibitors of ASIC1a we found, but only potentiators for ASIC2a. Flat aromatic structure of the headgroup determines inhibition of ASIC1a while "V-shape" structure of the hydrophobic moiety favors potentiation of ASIC2a. Moreover, for some series of monoamines there was a correlation between action on ASIC1a and ASIC2a, the weaker ASIC1a inhibition, the stronger ASIC2a potentiation. Decay of response was accelerated by ASIC1a inhibitors as well as by potentiators. All compounds potentiating ASIC2a slowed down desensitization. Our results suggest that hydrophobic amines cause complex action on ASICs.


Subject(s)
Acid Sensing Ion Channels/chemistry , Acid Sensing Ion Channels/metabolism , Amines , Hydrophobic and Hydrophilic Interactions , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclohexanes/chemistry , Cyclohexanes/metabolism , Structure-Activity Relationship
4.
Neuropharmacology ; 89: 1-10, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25196733

ABSTRACT

Acid-sensing ion channels (ASICs) are widely distributed in the peripheral and central nervous system. Although they are involved in many physiological functions, the actual processes that activate ASICs remain unclear. This is particularly true for brain ASICs, which produce only a transient response to a fast drop in pH and cannot mediate sustained current. Therefore, the search for ASIC inhibitors and, especially, potentiators/activators is important. We report that NMDA receptor channel blockers with a comparatively simple structure (9-aminoacridine, memantine, IEM-2117 and IEM-1921) potentiate and/or inhibit ASICs in submillimolar concentrations. The experiments were performed using the patch clamp technique on native ASICs from rat hippocampal interneurons and recombinant ASICs of different subunit compositions expressed in CHO cells. Native ASICs were potentiated by IEM-1921 and IEM-2117, and inhibited by memantine and 9-aminoacridine. Homomeric ASIC1a were inhibited by memantine, IEM-2117 and 9-aminoacridine while IEM-1921 was ineffective. In contrast, homomeric ASIC2a were potentiated by IEM-2117, memantine and IEM-1921, whereas 9-aminoacridine was inactive. The compounds caused a complex effect on ASIC3. 9-aminoacridine and IEM-1921 potentiated the steady-state response of ASIC3 and inhibited the peak component. IEM-2117 not only potentiated ASIC3-mediated currents caused by acidification but also evoked steady-state currents at neutral pH. Our results demonstrate that, depending on the subunit composition, ASICs can be activated or inhibited by simple compounds that possess only amino group and aromatic/hydrophobic moieties. This opens up the possibility to search for new ASIC modulators among a number of endogenous ligands.


Subject(s)
Acid Sensing Ion Channel Blockers/pharmacology , Acid Sensing Ion Channels/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Animals , CHO Cells , Cricetulus , Cyclohexylamines/pharmacology , Male , Memantine/pharmacology , Organ Culture Techniques , Rats , Rats, Wistar , Recombinant Proteins/metabolism
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