C5 methylation confers accessibility, stability and selectivity to picrotoxinin.

ABSTRACT: 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 (GABA_A) receptors) but maintains or increases antagonism of homologo

SUBMITTER: Tong G 

PROVIDER: S-EPMC10721898 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature