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

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• GABAA receptors are crucial inhibitory anion channels in the central nervous system.
• Positive allosteric modulators (PAMs) of GABAA receptors are vital therapeutic targets.
• Monoterpenes, like myrtenol, have emerged as novel modulators of GABAA receptors.

Purpose of the Study:

• To investigate the structure-activity relationship of myrtenol as a GABAA receptor PAM.
• To identify key structural elements responsible for myrtenol's modulatory effects.
• To explore scaffold modifications of myrtenol for optimized GABAA receptor activity.

Main Methods:

• Pharmacophore-based virtual screening to predict modulatory activity.
• Fluorescence-based compound analysis in transfected cells.
• Electrophysiological recordings (whole-cell configuration) to assess GABAergic currents.

Main Results:

• Scaffold modifications of myrtenol led to a loss of positive allosteric modulation.
• C-atoms 1 and 2 of the myrtenol backbone are critical for maintaining positive allosteric potential.
• Modifications at C-atom 2 or absence of the hydroxyl group at C-atom 1 significantly reduced GABAergic currents across multiple GABAA receptor subtypes.
• Some modified compounds exhibited non-specific inhibition of GABAergic responses.

Conclusions:

• The side chain modifications of myrtenol's bridged six-membered ring are essential for its modulatory potential at GABAA receptors.
• Specific structural features, particularly around C-atoms 1 and 2, dictate the activity of myrtenol derivatives.
• Understanding these structure-activity relationships can guide the development of novel GABAA receptor modulators.