Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation.

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autor(en): Milanos S, Künzel K, Gilbert D, Janzen D, Sasi M, Büttner A, Frimurer TM, Villmann C
Zeitschrift: Biological Chemistry
Jahr der Veröffentlichung: 2018
ISSN: 1431-6730
Sprache: Englisch


Abstract


GABAA receptors are ligand-gated anion channels

that form pentameric arrangements of various subunits.

Positive allosteric modulators of GABAA receptors

have been reported as being isolated either from plants

or synthesized analogs of known GABAA receptor targeting

drugs. Recently, we identified monoterpenes, e.g.

myrtenol as a positive allosteric modulator at α1β2 GABAA

receptors. Here, along with pharmacophore-based virtual

screening studies, we demonstrate that scaffold modifications

of myrtenol resulted in the loss of modulatory activity.

Two independent approaches, fluorescence-based

compound analysis and electrophysiological recordings

in whole-cell configurations were used for analysis

of transfected cells. C-atoms 1 and 2 of the myrtenol

backbone were identified as crucial to preserve positive

allosteric potential. A modification at C-atom 2 and lack

of the hydroxyl group at C-atom 1 exhibited significantly

reduced GABAergic currents at α1β2, α1β2γ, α2β3, α2β3γ

and α4β3δ receptors. This effect was independent of

the γ2 subunit. A sub-screen with side chain length and

volume differences at the C-atom 1 identified two compounds

that inhibited GABAergic responses but without

receptor subtype specificity. Our combined approach of

pharmacophore-based virtual screening and functional

readouts reveals that side chain modifications of the

bridged six-membered ring structure of myrtenol are

crucial for its modulatory potential at GABAA receptors.



FAU-Autoren / FAU-Herausgeber

Büttner, Andrea Prof. Dr.
Lehrstuhl für Lebensmittelchemie (Henriette-Schmidt-Burkhardt Lehrstuhl)
Gilbert, Daniel PD Dr.
Lehrstuhl für Medizinische Biotechnologie
Künzel, Katharina
Lehrstuhl für Medizinische Biotechnologie


Autor(en) der externen Einrichtung(en)
Julius-Maximilians-Universität Würzburg
University of Copenhagen


Zitierweisen

APA:
Milanos, S., Künzel, K., Gilbert, D., Janzen, D., Sasi, M., Büttner, A.,... Villmann, C. (2018). Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation. Biological Chemistry. https://dx.doi.org/10.1515/hsz-2017-0262

MLA:
Milanos, Sinem, et al. "Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation." Biological Chemistry (2018).

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Zuletzt aktualisiert 2019-02-01 um 05:10