Wise L D, Pattison I C, Butler D E, DeWald H A, Lewis E P, Lobbestael S J, Tecle H, Coughenour L L, Downs D A, Poschel B P
J Med Chem. 1985 Dec;28(12):1811-7. doi: 10.1021/jm00150a011.
8-[3-[Bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8- triazaspiro[4.5]decan-4-one (3) and related compounds have been shown to have antipsychotic profiles in biochemical and behavioral pharmacological test models. The dose of 3 necessary to produce catalepsy in rats is much greater than that required for activity in behavioral tests predictive of antipsychotic efficacy, for example the suppression of high base line medial forebrain bundle self-stimulation in rats. This suggests that 3 would have a reduced propensity for neurological side effects. The effects of substitution on the 1-phenyl moiety and on the N-3 nitrogen atom of the triazaspirodecanone portion of 3 were examined. Results from this study suggest that behavioral activity is sensitive to substituents on the 1-phenyl moiety while substituents on the N-3 nitrogen are more generally tolerated. In both rats and squirrel monkeys compound 3 was found to have a similar separation between doses inhibiting Sidman avoidance activity and those causing catalepsy. However, in an extrapyramidal side effect (EPS) test model using haloperidol-sensitized cebus monkeys, 3 elicited signs of EPS at doses approximating those previously determined to be efficacious.
8-[3-[双(4-氟苯基)氨基]丙基]-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-4-酮(3)及相关化合物在生化和行为药理学测试模型中已显示出具有抗精神病特性。在大鼠中产生僵住症所需的3的剂量远大于在预测抗精神病疗效的行为测试中产生活性所需的剂量，例如抑制大鼠高基线内侧前脑束自我刺激。这表明3产生神经副作用的倾向会降低。研究了3的1-苯基部分和三氮杂螺癸烷酮部分的N-3氮原子上的取代作用。该研究结果表明，行为活性对1-苯基部分上的取代基敏感，而N-3氮上的取代基更普遍地被耐受。在大鼠和松鼠猴中，发现化合物3在抑制西德曼回避活动的剂量和引起僵住症的剂量之间具有相似的差异。然而，在使用氟哌啶醇致敏的卷尾猴的锥体外系副作用(EPS)测试模型中，3在接近先前确定为有效的剂量时引发了EPS体征。
