PICRODENDRIN AND RELATED TERPENOID ANTAGONISTS REVEAL STRUCTURAL DIFFERENCES BETWEEN IONOTROPIC GABA RECEPTORS OF MAMMALS AND INSECTS

Twenty-eight picrotoxane terpenoids, including picrodendrins isolated from the Euphorbiaceae plant, Picrodendron baccatum (L.) Krug and Urba n, have been evaluated for their ability to inhibit the specific bindi ng of [H-3]EBOB, the noncompetitive antagonist of ionotropic GABA rece ptors, to rat-brain and housefly (Musca domestica L.)-head membranes. Picrodendrin Q was the most potent competitive inhibitor of[H-3]EBOB b inding, with IC50 values of 16 nM (rat) and 22 nM (Musca). We find tha t the spiro gamma-butyrolactone moiety at the 13-position, which conta ins a carbonyl group conjugated with an unsaturated bond, and the subs tituents at the 4-position play important roles in the interaction of picrodendrins with their binding site in rat receptors. In contrast, s uch structural features are not strictly required in the case of the i nteraction with Musca receptors; the spiro saturated gamma-butyrolacto ne moiety at the 13-position, which bears the 16-sp(3) carbon atom, an d the hydroxyl groups at various positions are somewhat tolerated. Qua ntitative structure-activity studies have clearly shown that the elect ronegativity of the 16-carbon atom and the presence or absence of the 4- and 8-hydroxyl groups are important determinants of the potency of nor-diterpenes in Musca receptors, while the negative charge on the 17 -carbonyl oxygen atom is likely important in the case of rat receptors . These findings indicate that there are significant differences betwe en the structures of the complementary binding sites in rat GABA recep tors and Musca GABA receptors. We also infer differences between nativ e Musca GABA receptors and the Drosophila Rdl subunit-containing homo- oligomeric GABA receptors in the structures of their binding sites. (C ) 1998 Elsevier Science Ltd. All rights reserved.