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

Milanos S, Künzel K, Gilbert D, Janzen D, Sasi M, Büttner A, Frimurer TM, Villmann C (2018)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2018

Journal

Biological Chemistry Walter de Gruyter

DOI: 10.1515/hsz-2017-0262

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.

Authors with CRIS profile

Katharina Künzel Lehrstuhl für Medizinische Biotechnologie Daniel Gilbert Lehrstuhl für Medizinische Biotechnologie Andrea Büttner Lehrstuhl für Aroma- und Geruchsforschung

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) University of Copenhagen DK Denmark (DK)

How to cite

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).

BibTeX: Download