GABA in VR: Common Therapeutics Involved in Arousal Inhibit GABAaR Activation
GABAa receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAa receptor-negative allosteric modulators (GABAaRNAMs) can increase arousal and induce seizures. Motivated by their studies with patients with hypersomnia, and the discovery that two GABAaRNAMs can restore the Excitation/Inhibition balance in vitro and arousal in vivo, this research team chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. The computational modeling of modulator–receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. The findings of the study suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance.
Reference:
Kaplan et al (2023) Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAaR Activation. Biomolecules. 2023 Feb 15;13(2):365. doi:
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