C5 methylation confers accessibility, stability and selectivity to picrotoxinin

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Synthetic Organic Chemistry

Background:

• Picrotoxinin (PXN) is a known neurotoxin affecting ion channels.
• Limited structure-activity relationship (SAR) studies exist for PXN due to synthetic complexity.
• Advances in total synthesis enable new explorations of PXN analogs.

Purpose of the Study:

• To explore PXN analogs for selective targeting of mammalian versus insect ion channels.
• To conduct the first SAR studies on PXN, leveraging modern synthetic techniques.
• To identify PXN modifications that enhance selectivity for invertebrate GABA-gated chloride channels (RDL) over vertebrate GABA_A receptors.

Main Methods:

• Synthesis of two parallel series of PXN analogs.
• Investigating the impact of structural modifications, specifically C5 methylation, on PXN properties.
• Assessing the functional activity of analogs against mammalian GABA_A and invertebrate RDL receptors.

Main Results:

• A C5 methyl group significantly stabilizes PXN, preventing secondary hydrolysis and increasing plasma half-life.
• C5 methylation reduces potency against mammalian GABA_A receptors but maintains or enhances activity against invertebrate RDL receptors.
• Optimal 5-methyl PXN analogs alter binding pose in GABA_ARs, disrupting hydrogen bonding networks.

Conclusions:

• The C5 methyl group is crucial for enhancing selectivity between mammalian and insect ion channels.
• These findings represent the first SAR studies to identify PXN modifications that improve the GABA_A-RDL selectivity index.
• The synthetic accessibility of 5-methyl PXN analogs facilitates further research and development.