Bicyclophosphorothionate antagonists exhibiting selectivity for housefly GABA receptors

Abstract

2,6,7‐Trioxa‐1‐phosphabicyclo[2.2.2]octane 1‐sulfides (bicyclophosphorothionates) with various C1–4 alkyl groups at the 3‐ and 4‐positions were synthesized and tested for their ability to compete with [3H]4′‐ethynyl‐4‐n‐propylbicycloorthobenzoate (EBOB), a non‐competitive antagonist of γ‐aminobutyric acid (GABA) receptors, for specific binding to rat‐brain and housefly‐head membranes, and for their insecticidal activity against houseflies. Among the 3,4‐substituted analogues, 20 compounds were selectively active for housefly GABA receptors versus rat GABA receptors. The 3‐alkyl groups of C3 length and the 4‐alkyl groups of C4 length were tolerated in housefly receptors, whereas such bulky substituents were deleterious in rat receptors. The 4‐isobutyl‐3‐isopropyl analogue was the most potent in housefly receptors (IC50 = 45.2 nM), and tert‐butylbicyclophosphorothionate (TBPS), with the 4‐tert‐butyl group and no 3‐substituent, was the most potent in rat receptors (IC50 = 62.2 nM). Their receptor selectivities (rat IC50/housefly IC50) were 52 and 0.038, respectively. The insecticidal activity (LD50) of 20 active analogues was well correlated with their potency (IC50) in inhibiting [3H]EBOB binding to housefly‐head membranes (r = 0.93). The results obtained in the present study indicate that the introduction of appropriate alkyl groups into the 3‐ and 4‐positions of bicyclophosphorothionate leads to non‐competitive antagonists with increased affinity and selectivity for housefly ionotropic GABA receptors versus rat GABAA receptors. © 1999 Society of Chemical Industry

Chloride channels as tools for developing selective insecticides

“…Addition of alkyl side chains to the trioxabicyclooctane moiety in the 3-position ( Fig. 1) resulted in good synergized insecticidal activity, and the compounds had selectivity ratios over 50 for [ 3 H]EBOB binding (rat IC 50 /housefly IC 50 ), in- Archives of Insect Biochemistry and Physiology dicating differential receptor recognition (Ju and Ozoe, 1999). PTX was the first described chloride channel blocker, and other PTX-like natural products are structurally-related terpenoids, including the tutins and picrodendrins (Fig.…”

Phenylpyrazole Insecticide Photochemistry, Metabolism, and GABAergic Action: Ethiprole Compared with Fipronil

“…The homogenate was filtered through four layers of cheesecloth and centrifuged at 1500g for 10 min, and the supernatant was filtered again and centrifuged at 23 000g for 25 min. The pellet was resuspended in the sucrose-Tris-hydrochloric acid buffer, maintained at 5 °C for 25 min (26), and centrifuged at 23 000g for 25 min. Finally, the pellet was suspended in 10 mM sodium phosphate buffer (pH 7.5) containing 300 mM sodium chloride and used for binding assay.…”

Mechanistic insights into the selectivity of bicyclophosphorothionate antagonists for housefly versus rat GABA receptors

“…Aiming to develop insecticides with novel structures, we previously synthesized a series of 3,4-disubstituted 2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-sulfides (bicyclophosphorothionates) and investigated their abilities to compete with the noncompetitive GABAR antagonist [ 3 H]EBOB (4 0 -ethynyl-4-n-propylbicycloorthobenzoate) for the binding site in rat brain-and housefly head-membranes, and the structure-activity relationships of some analogs were studied using conventional comparative molecular field analysis (CoMFA) method. 21,22 As a result, we found that bicyclophosphorothionates bearing different substituents at the 3-and 4-positions exhibit various degrees of selectivity between housefly and rat GABARs. Although molecular cloning studies have provided insights into the molecular structures of GABARs, it remains elusive how GABAR-targeting insecticides selectively inhibit the functions of insect GABARs.…”