Ju X L, Ozoe Y
Department of Life Science and Biotechnology, Shimane University, Matsue, Japan.
Bioorg Med Chem. 2000 Sep;8(9):2337-41. doi: 10.1016/s0968-0896(00)00162-0.
The enantiomers of 4-tert-butyl-3-isopropyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2 ]octane 1-sulfide (TBIPPS) were prepared in nine steps from diethyl tert-butylmalonate, and their abilities to compete with [3H]1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2 ]octane (EBOB), a noncompetitive antagonist of ionotropic gamma-aminobutyric acid (GABA) receptors, at their binding site were investigated using rat brain and housefly head membranes. The (S)-(-)-isomer of TBIPPS (IC50 = 398 nM) was more potent than was the (R)-(+)-isomer of TBIPPS (IC50 = 1220 nM) in rat receptors, while the potencies of (S)-TBIPPS 104 nM) and (R)-TBIPPS (IC50 = 94.4 nM) in housefly receptors were almost the same. The different enantiospecificities of rat and housefly receptors indicate that the three-dimensional structure of the binding site might be different between these receptors. In a region of the rat binding site there might be a steric bulk that interacts less favorably with (R)-TBIPPS than with (S)-TBIPPS, while in the corresponding region of the housefly binding site there might not be such a steric bulk that leads to specificity for these compounds.
4-叔丁基-3-异丙基-2,6,7-三氧杂-1-磷杂双环[2.2.2]辛烷1-硫化物（TBIPPS）的对映体由叔丁基丙二酸二乙酯经九步反应制得，利用大鼠脑和家蝇头部膜片研究了它们在离子型γ-氨基丁酸（GABA）受体结合位点与[3H]1-(4-乙炔基苯基)-4-正丙基-2,6,7-三氧杂双环[2.2.2]辛烷（EBOB，一种离子型GABA受体的非竞争性拮抗剂）竞争的能力。在大鼠受体中，TBIPPS的（S）-（-）-异构体（IC50 = 398 nM）比（R）-（+）-异构体（IC50 = 1220 nM）更有效，而在家蝇受体中，（S）-TBIPPS（IC50 = 104 nM）和（R）-TBIPPS（IC50 = 94.4 nM）的效力几乎相同。大鼠和家蝇受体不同的对映体特异性表明，这些受体结合位点的三维结构可能不同。在大鼠结合位点的一个区域，可能存在一个空间位阻，与（R）-TBIPPS的相互作用不如与（S）-TBIPPS有利，而在家蝇结合位点的相应区域，可能不存在导致对这些化合物具有特异性的这种空间位阻。
