Rational Search for Betaine/GABA Transporter 1 Inhibitors─In Vitro Evaluation of Selected Hit Compound.

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Gamma-aminobutyric acid (GABA) neurotransmission is crucial for maintaining homeostasis.
• Dysregulation of GABA signaling is linked to neurological and psychiatric conditions like epilepsy and anxiety.
• GABA transporters (GAT1, BGT1, GAT2, GAT3) regulate GABA levels; inhibiting them can increase GABA neurotransmission.

Purpose of the Study:

• To discover novel inhibitors targeting the understudied betaine/GABA transporter 1 (BGT1).
• To evaluate the therapeutic potential of BGT1 inhibition.
• To identify specific compounds that selectively inhibit BGT1 activity.

Main Methods:

• Multilevel virtual screening was employed to identify potential BGT1 inhibitors.
• Compound 9 was selected and characterized for its inhibitory activity against various GABA transporters (BGT1, GAT1, GAT2, GAT3).
• Mutagenesis studies (E52A, E52Y, Q299L) were used to confirm the binding mode of compound 9 to human BGT1.

Main Results:

• Compound 9 demonstrated preferential inhibition of BGT1 with an IC50 of 13.9 μM.
• It showed moderate inhibitory activity against GAT3 and negligible activity against GAT1 and GAT2.
• Compound 9 exhibited no affinity for major GABA_A receptor subtypes, was non-toxic to astrocytes, and displayed neuroprotective effects in SH-SY5Y cells.

Conclusions:

• Compound 9 is a promising selective BGT1 inhibitor.
• It represents a valuable lead compound for developing novel therapeutics targeting BGT1.
• Further research into BGT1 inhibition holds potential for treating neurological and psychiatric disorders.