Structure–Activity Relationships of seco-Prezizaane Terpenoids in γ-Aminobutyric Acid Receptors of Houseflies and Rats

Abstract

Thirteen seco-prezizaane terpenoids isolated from star anise species ( Illcium floridanum, Illcium parviflorum, and Illcium verum) were investigated for their ability to inhibit the specific binding of [ 3H]4′-ethynyl-4- n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of γ-aminobutyric acid (GABA) receptors, to housefly-head and rat-brain membranes. Veranisatin A was found to be the most potent inhibitor in both membranes, with an IC 50 fly of 78.5 nM and an IC 50 rat of 271 nM, followed by anisatin (IC 50 fly=123 nM; IC 50 rat=282 nM). Six of the other 11 tested compounds were effective only in housefly-head membranes. Pseudoanisatin proved to display a high (>26-fold) selectivity for housefly versus rat GABA receptors (IC 50 fly=376 nM; IC 50 rat >10,000 nM). Although pseudoanisatin does not structurally resemble EBOB, Scatchard plots indicated that the two compounds bind to the same site in housefly receptors. Anisatin and pseudoanisatin exhibited moderate insecticidal activity against German cockroaches. Comparative molecular field analysis (CoMFA), a method of three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis, demonstrated that seco-prezizaane terpenoids can bind to the same site as do picrotoxane terpenoids such as picrotoxinin and picrodendrins, and the CoMFA maps allowed us to identify the parts of the molecules essential to high activity in housefly GABA receptors.