C5 methylation confers accessibility, stability and selectivity to picrotoxinin

by Selleckchem | Feb 02 2024

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.

Comments:

This is a detailed exploration of how small alterations in the structure of picrotoxinin analogs can lead to significant changes in their biological effects. Researchers investigated two series of these analogs, uncovering leads that show selectivity between mammalian and insect ion channels. Despite picrotoxinin's long history, these studies represent the first systematic exploration of its structure-activity relationship (SAR), made feasible by advancements in total synthesis techniques.

One key finding was the discovery of the stabilizing effect of a C5 methyl group, preventing C15 alcoholysis by destabilizing an intermediate conformer. This alteration extended the compound's half-life in plasma by inhibiting a secondary hydrolysis pathway. The C5 methylation also impacted potency against vertebrate ion channels (GABAA receptors), reducing it, while maintaining or even enhancing antagonism against invertebrate GABA-gated chloride channels (RDL receptors).

The optimized 5MePXN analogs seem to induce a change in how PXN binds to GABAA receptors by disrupting a hydrogen bond network. The synthetic simplification of 5MePXN played a crucial role in uncovering these effects and understanding the role of the C5 methyl in channel selectivity. Importantly, these studies represent the first SAR investigations that identify modifications to PXN, leading to an increased GABAA-RDL selectivity index.

This research demonstrates how minor structural modifications in complex molecules can lead to profound changes in both synthesis strategy and functional properties, shedding light on new possibilities for designing compounds with enhanced selectivity for specific biological targets.