Liao Y, Venhuis B J, Rodenhuis N, Timmerman W, Wikström H, Meier E, Bartoszyk G D, Böttcher H, Seyfried C A, Sundell S
Department of Medical Biochemistry, University of Göteborg, Box 440, SE-405 30 Göteborg, Sweden.
J Med Chem. 1999 Jun 17;42(12):2235-44. doi: 10.1021/jm991005d.
A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.
合成了一系列2-或8-三氟甲磺酰氧基（TfO）以及2-或8-甲磺酰氧基（MsO）的11-哌嗪基二苯并二氮杂卓、二苯并恶嗪和二苯并噻嗪，并在药理学模型中评估了它们类似氯氮平的潜在性质。在受体结合试验中，二苯并氮杂卓的2-TfO类似物（18a，GMC2-83；24，GMC3-06；以及先前报道的GMC1-169，9a）具有与氯氮平相当的谱图，作用于多种中枢神经系统受体，但它们缺乏M1受体亲和力。将2-TfO引入氯氮平得到化合物9e（GMC61-39），其具有与氯氮平相似的结合谱图，包括具有M1受体亲和力。有趣的是，MsO类似物以及8-TfO类似物具有无或弱的多巴胺能和5-羟色胺能亲和力，但所有8-磺酰氧基类似物都具有M1亲和力。在旨在表明潜在抗精神病疗效和诱导锥体外系反应倾向的行为学研究中，2-TfO类似物以剂量依赖性方式有效阻断阿扑吗啡诱导的小鼠攀爬，9a的ED50值（mg/kg）腹腔注射为2.1，18a口服为1.3，24腹腔注射为2.6，9e腹腔注射为8.2。另一方面，它们在表明大鼠僵住症的ED50值（mg/kg）方面表现出明显的剂量差异（9a腹腔注射>44，18a口服28，24腹腔注射30，9e腹腔注射>50），因此与典型抗精神病药物如氟哌啶醇和异氯氮平相比，具有更有利的治疗指数（K/A，ED50攀爬/ED50僵住症）。此外，在离体L-多巴积累模型中，化合物18a也被证明是一种口服有效的多巴胺拮抗剂，ED50值为0.7mg/kg口服。本研究有助于11-哌嗪基二苯并氮杂卓的构效关系研究，并且11-哌嗪基二苯并氮杂卓的2-TfO类似物是有前景的候选药物，可作为类似氯氮平的非典型抗精神病药物，诱导锥体外系反应的倾向较低。
