para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter
| Autor: | Gerhard F. Ecker, Walter Sandtner, Marco Niello, Kathrin Jäntsch, Leila H. Ayatollahi, Daniela Cintulova, Nicholas V. Cozzi, Marko D. Mihovilovic, Michael Freissmuth, Eva Hellsberg, Marion Holy, Harald H. Sitte |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Neurotransmitter transporter Models Molecular Allosteric modulator Cathinone Allosteric regulation Methcathinone 03 medical and health sciences Cellular and Molecular Neuroscience Structure-Activity Relationship 0302 clinical medicine Serotonin Agents medicine Humans Computer Simulation Amphetamine Serotonin transporter Pharmacology Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Propiophenones Binding Sites biology Chemistry Electrophysiological Phenomena Molecular Docking Simulation Kinetics 030104 developmental biology Monoamine neurotransmitter HEK293 Cells biology.protein Biophysics 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuropharmacology. 161 |
| ISSN: | 1873-7064 |
| Popis: | The transporters for dopamine (DAT) and serotonin (SERT) are important targets in the treatment of psychiatric disorders including major depression, anxiety and attention-deficit hyperactivity disorder. Drugs acting at these transporters can act as inhibitors or as releasers. In addition, it has been recently appreciated that some compounds are less efficacious releasers than amphetamine. Thus, they are classified as partial releasers. Compounds can act on both SERT and DAT or display exquisite selectivity for either SERT or DAT, but the structural basis for selectivity is poorly understood. The trifluoromethyl-substitution of methcathinone in the para-position has been shown to dramatically shift the selectivity of methcathinone (MCAT) towards SERT. Here, we examined MCAT, para-trifluoromethyl-methcathinone (pCF3MCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF3-substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the pCF3group, but not of other substituents with larger van der Waal's volume, lipophilicity or polarity, converted the DAT-selective MCAT into a SERT-selective partial releaser. Electrophysiological and superfusion experiments, together with kinetic modelling, showed that pCF3MCAT, but not MCAT, trapped a fraction of SERTs in an inactive state by occupying the S2-site. These findings define a new mechanism of action for partial releasers, which is distinct from the other two known binding modes underlying partial release. Our observations highlight the fact that the substrate permeation pathway of monoamine transporters supports multiple binding modes, which can be exploited for drug design. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'. |
| Databáze: | OpenAIRE |
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