Li Q X, Casida J E
Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112, USA.
Bioorg Med Chem. 1995 Dec;3(12):1667-74. doi: 10.1016/0968-0896(95)00152-2.
The noncompetitive blocker (NCB) site of the gamma-aminobutyric acid (GABA)-gated chloride channel is the target for many important insecticides and potent convulsants. This site is specifically blocked by 3H ethynylbicycloorthobenzoate (3H EBOB) and other trioxabicyclooctane radioligands and might be suitable for affinity probes with an appropriate heterocyclic substituent and linker moiety. Optimal potency at the NCB site is achieved with 5e-tert-butyl-2e-[4-(substituted-ethynyl)phenyl]-1,3-dithianes+ ++ compared with analogs in which the butyldithiane portion is replaced with butyldithiane-sulfoxide or -sulfone, n-propyltrioxabicyclooctane or dioxatricyclododecene. Three positions were examined for coupling the linker and dithiane: C-2 of the dithiane; a branched substituent within the alkynyl moiety; the terminus of a straight chain extension from the ethynyl group, which proved to be the best. Optimized linkers for addition to the ethynylphenyldithiane to achieve appropriate length and fit within the active site, i.e. receptor potency, are CH2OCH2C(O)SCH2CH2 (SH or NH2) and the corresponding thiolates and amides. Several compounds with these spacers block the chloride channel, measured as inhibition of 3H EBOB binding, at 4-50 nM.
γ-氨基丁酸（GABA）门控氯离子通道的非竞争性阻断剂（NCB）位点是许多重要杀虫剂和强效惊厥剂的作用靶点。该位点可被3H-乙炔基双环邻苯二甲酸酯（3H EBOB）和其他三氧杂双环辛烷放射性配体特异性阻断，并且可能适用于带有合适杂环取代基和连接基团的亲和探针。与丁基二硫烷部分被丁基二硫烷亚砜或砜、正丙基三氧杂双环辛烷或二氧杂三环十二烯取代的类似物相比，5e-叔丁基-2e-[4-（取代乙炔基）苯基]-1,3-二硫烷在NCB位点具有最佳效力。研究了连接基团与二硫烷连接的三个位置：二硫烷的C-2位；炔基部分内的支链取代基；乙炔基直链延伸的末端，结果证明该末端是最佳位置。为了达到合适的长度并适配活性位点（即受体效力）而添加到乙炔基苯基二硫烷上的优化连接基团为CH2OCH2C（O）SCH2CH2（SH或NH2）以及相应的硫醇盐和酰胺。几种带有这些间隔基团的化合物以4 - 50 nM的浓度阻断氯离子通道，这通过对3H EBOB结合的抑制来测定。
