para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter

Author(s)
Marco Niello, Daniela Cintulova, Eva Hellsberg, Kathrin Jäntsch, Marion Holy, Leila H. Ayatollahi, Nicholas V. Cozzi, Michael Freissmuth, Walter Sandtner, Gerhard F. Ecker, Marko D. Mihovilovic, Harald H. Sitte
Abstract

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 (p–CF

3

–MCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF

3

-substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the p–CF

3

–group, 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 p–CF

3

–MCAT, 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.

Organisation(s)
Department of Pharmaceutical Chemistry
External organisation(s)
Medizinische Universität Wien, Technische Universität Wien, University of Wisconsin, Madison
Journal
Neuropharmacology
ISSN
0028-3908
DOI
https://doi.org/10.1016/j.neuropharm.2019.04.021
Publication date
04-2019
Peer reviewed
Yes
Austrian Fields of Science 2012
Pharmaceutical chemistry
Keywords
ASJC Scopus subject areas
,
Portal url
https://ucris.univie.ac.at/portal/en/publications/paratrifluoromethylmethcathinone-is-an-allosteric-modulator-of-the-serotonin-transporter(78bb56f9-aec4-4ee4-9d6d-ad8a50046d0e).html