2-Aryl-5-tert-butyl-1,3-dithianes and their S-oxidation products:  structure-activity relationships of potent insecticides acting at the GABA-gated chloride channel

Wacher, Vincent J.; Toia, Robert F.; Casida, John E.

doi:10.1021/jf00015a028

Cited by 31 publications

(20 citation statements)

References 24 publications

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“…The highly insecticidal orthobenzoate EBOB (Figure 96.10) proved to be the best ligand for the insect GABA-receptor chloride ionophore, and [ 3 H]-EBOB has been used subsequently in binding displacement studies with numerous putative channel blockers at the PTX binding site. Attempts to simplify the orthobenzoate ring system of these potent cage convulsants and the search for structural changes to confer selective toxicity in favor of mammals versus insects produced numerous insecticidal dithianes, oxathianes, and their sulfoxides and sulfones (Palmer and Casida, 1995;Wacher et al, 1992). Figure 96.10 further shows the convergence of structural changes between partly (Brooks and Mace, 1987) and totally (Ozoe et al, 1990) dechlorinated alpha-endosulfan (1, Figure 96.10) (which surprisingly retains measurable housefly toxicity (LD 50 , ca.…”

Section: Structural Convergence Of Cyclodienes and Their Dechlorinatementioning

confidence: 97%

Interactions with the Gamma-Aminobutyric Acid A-Receptor

Brooks¹

2010

Hayes' Handbook of Pesticide Toxicology

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Section: Structural Convergence Of Cyclodienes and Their Dechlorinatementioning

confidence: 97%

Interactions with the Gamma-Aminobutyric Acid A-Receptor

Brooks¹

2010

Hayes' Handbook of Pesticide Toxicology

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“…The syntheses of the dithianes and S-oxide products (compounds 1 and 2 as well as the other dithianes in Table 1) followed the methods of Casida and co-workers [9,10,[13][14][15]. Although a published synthetic sequence, the preparation of these dithiane oxides required careful attention to separation of isomers and identification of sulfur oxidation states.…”

Section: Chemistrymentioning

confidence: 99%

“…Although radiochemical syntheses were successful [7][8], these radioligands showed no potential as in vivo imaging agents due to rapid hydrolysis in the blood, low brain uptake, and uniform distributions. Subsequent efforts targeted substituted 5-tert-butyl-2-phenyl-1,3dithiane derivatives and their oxides, which have demonstrated much more resistance to hydrolysis and exhibit high biological activity as insecticidal agents acting upon the GABAionophore binding site [9][10]. Radiolabeling of this class of molecules was demonstrated using carbon-11, fluorine-18 and iodine-125 [11][12].…”

Section: Introductionmentioning

confidence: 99%

“…The published structure-activity relationship data for the 5-tert-butyl-2-phenyl-1,3-dithianes include a variety of aryl ring substituents, sulfur oxidation states, and stereochemistry (both at C-2 carbon and sulfur atoms), with biological data comprised of a mixture of in vitro derived binding affinities (often using different competing radioligands) and in vivo determined toxicities to insects [9,10,[13][14][15]. To help identify potential radioligand candidates, we prepared a short series of representative compounds (Table 1) amenable to labeling with PET radionuclides and evaluated them for in vitro binding affinities using a consistent binding assay with the radioligand [ 3 H]EBOB (4′-ethynyl-4-n-[2,3-3 H 2 ]propylbicycloorthobenzoate).…”

Section: Introductionmentioning

confidence: 99%

“…To help identify potential radioligand candidates, we prepared a short series of representative compounds (Table 1) amenable to labeling with PET radionuclides and evaluated them for in vitro binding affinities using a consistent binding assay with the radioligand [ 3 H]EBOB (4′-ethynyl-4-n-[2,3-3 H 2 ]propylbicycloorthobenzoate). Building on our prior experiences, as well as the published structure-activity data [9,10,[13][14][15], interest was then focused on the trans-isomers with the 2-methyl substituents and oxidized sulfurs atoms. From this series we identified the 4′-(3-fluoropropynyl)-substituted compounds 1 and 2 as potential candidates for fluorine-18 labeling.…”

Section: Introductionmentioning

confidence: 99%

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5-tert-Butyl-2-(4′-[18F]fluoropropynylphenyl)-1,3-dithiane oxides: potential new GABAA receptor radioligands

Jung

Snyder

et al. 2008

Nuclear Medicine and Biology

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As potential new ligands targeting the binding site of gamma-aminobutyric acid (GABA) receptor ionophore, trans-5-tert-butyl-2-(4'-fluoropropynylphenyl)-2-methyl-1,1-dioxo-1,3-dithiane (1) and cis/trans-5-tert-butyl-2-(4'-fluoropropynylphenyl)-2-methyl-1,1,3,3-tetroxo-1,3-dithiane (2) were selected for radiolabeling and initial evaluation as in vivo imaging agents for positron emission tomography (PET). Both compounds exhibited identical high in vitro binding affinities (K(i)=6.5 nM). Appropriate tosylate-substituted ethynyl precursors were prepared by multistep syntheses involving stepwise sulfur oxidation and chromatographic isolation of desired trans isomers. Radiolabeling was accomplished in one step using nucleophilic [(18)F]fluorination. In vivo biodistribution studies with trans-[(18)F]1 and trans-[(18)F]2 showed significant initial uptake into mouse brain and gradual washout, with heterogeneous regional brain distributions and higher retention in the cerebral cortex and cerebellum and lower retention in the striatum and pons-medulla. These regional distributions of the new radioligands correlated with in vitro and ex vivo measures of standard radioligands binding to the ionophore- and benzodiazepine-binding sites of GABA(A) receptor in rodent brain. A comparison of these results with previously prepared radiotracers for other neurochemical targets, including successes and failures as in vivo radioligands, suggests that higher-affinity compounds with increased retention in target brain tissues will likely be needed before a successful radiopharmaceutical for human PET imaging can be identified.

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Heterocyclic Insecticides Acting at the GABA-Gated Chloride Channel: 5-Alkyl-2-arylpyrimidines and -1,3-thiazines

Pulman

Smith²,

Larkin³

et al. 1996

Pestic. Sci.

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5-tert-Butyl-2-(4-ethynylphenyI)pyrimidine and the corresponding 2,5-disubstituted-4H-1,3-thiazine block the GABA-gated chloride channel at c.20 and c.200 nM, respectively, measured as 50% inhibition of the binding of 1-(4-ethynylphenyl)-4-[3H]propyl-2,6,7-trioxabicyclo[2.2.2]octane (4-ethynyl-4-n-[3H]propylbicycloorthobenzoate; C3H]EB0B) in house fly and mouse brain membranes, and they are also toxic to topically-treated flies with LD,, values of 6-27 pg g-' alone and 2-6 pg g-' with piperonyl butoxide (PB) as synergist. In the pyrimidine series, the general pattern of effectiveness of substituents in the 5-position is tert-butyl > isopropyl z cyclohexyl z cyclopropyl > methyl, phenyl and 3-and 4-fluorophenyl, and in the 2-position is 4-ethynylphenyl % 4-bromophenyl. These planar pyrimidines and nearly-planar 4H-1,3-thiazines with 2-ethynylphenyl or 2-bromophenyl and 5-tert-butyl or 5-isopropyl substituents are more effective than the corresponding 6H-1,3-thiazine, 6-oxo-1,3-thiazines and 4,6-dioxo-1,3-thiazine examined, but they are less active than the analogous conformationally flexible trans-1,3-dioxanes and -1,3-dithianes. The heterocyclic moiety confers a region of high electron density and positions the 2-and 5-substituents in a linear or parallel relationship for optimal affinity at the receptor. Two observations indicate that the new pyrimidines and thiazines probably act as chloride channel blockers. First, the poisoning signs are identical to those of EBOB in both mice and house flies. Second, each of the pyrimidines, thiazines and dioxanes falls on the same correlation line for inhibition of C3H]EBOB binding and toxicity to house flies (with PB) as that obtained earlier for EBOB analogs, dithianes and polychlorocycloalkanes, suggesting that they all act at the same or closely coupled binding sites in the GABA-gated chloride channel.

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2-Aryl-5-tert-butyl-1,3-dithianes and their S-oxidation products: structure-activity relationships of potent insecticides acting at the GABA-gated chloride channel

Cited by 31 publications

References 24 publications

Interactions with the Gamma-Aminobutyric Acid A-Receptor

Interactions with the Gamma-Aminobutyric Acid A-Receptor

5-tert-Butyl-2-(4′-[18F]fluoropropynylphenyl)-1,3-dithiane oxides: potential new GABAA receptor radioligands

Heterocyclic Insecticides Acting at the GABA-Gated Chloride Channel: 5-Alkyl-2-arylpyrimidines and -1,3-thiazines

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