Di Fabio R, Capelli A M, Conti N, Cugola A, Donati D, Feriani A, Gastaldi P, Gaviraghi G, Hewkin C T, Micheli F, Missio A, Mugnaini M, Pecunioso A, Quaglia A M, Ratti E, Rossi L, Tedesco G, Trist D G, Reggiani A
Glaxo Wellcome S.p.A., Medicines Research Centre, Verona, Italy.
J Med Chem. 1997 Mar 14;40(6):841-50. doi: 10.1021/jm960644a.
A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.
合成了一系列在吲哚核C-3位带有合适链的吲哚-2-羧酸盐，并通过[³H]甘氨酸结合试验评估其体外亲和力，以及通过抑制小鼠中由N-甲基-D-天冬氨酸（NMDA）诱导的惊厥来评估其体内效力。3-[2-[(苯胺基)羰基]乙烯基]-4,6-二氯吲哚-2-羧酸（8）是士的宁不敏感甘氨酸结合位点的拮抗剂（对[³H]TCP结合的非竞争性抑制，pA₂ = 8.1），对甘氨酸结合位点显示出纳摩尔亲和力（pKi = 8.5），同时具有高谷氨酸受体选择性（相对于在NMDA、AMPA和海人藻酸结合位点的亲和力>1000倍）。当通过静脉注射和口服途径给药时，这种吲哚衍生物抑制了小鼠中由NMDA诱导的惊厥（ED₅₀分别为0.06和6 mg/kg）。研究了C-3侧链末端苯环上取代基的影响。定量构效关系分析表明，pKi值随取代基的亲脂性和空间体积降低而降低，并随末端苯环对位存在的基团的给电子共振效应增加而增加。根据这些结果，C-3侧链的末端苯环应位于有限大小的非疏水口袋中，完善了与NMDA受体相关的甘氨酸结合位点的药效团模型。
