5-tert-Butyl-2-(4-ethynylphenyI)pyrimidine and the corresponding 2,5disubstituted-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-
) 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 2ethynylphenyl 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 5substituents 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.