Wise L D, Pattison I C, Butler D E, DeWald H A, Lewis E P, Lobbestael S J, Nordin I C, Poschel B P, Coughenour L L
J Med Chem. 1985 May;28(5):606-12. doi: 10.1021/jm50001a013.
On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).
基于突触后多巴胺能拮抗剂药效基团的结构模型，合成了一系列1-[3-(二芳基氨基)丙基]哌啶及其相关化合物，并对其潜在的抗精神病活性进行了评估。为了快速测定活性，首先在体外对目标化合物进行[3H]氟哌啶醇结合抑制筛选，并在体内进行运动活性测试。通过使用高基线内侧前脑束自我刺激抑制测试模型，更准确地测定了从初步筛选中鉴定出的化合物在大鼠中的行为功效。使用大鼠僵住症方法评估了这些化合物引起锥体外系副作用的倾向。基于这些测试模型，我们已经表明1-(4,4-二芳基丁基)哌啶的次甲基碳可以有利地被氮原子取代。1-[3-(二芳基氨基)丙基]哌啶的僵住症作用比相应的1-(4,4-二芳基丁基)哌啶小。有效剂量和僵住症剂量之间差异最大的化合物是8-[3-[双(4-氟苯基)氨基]丙基]-1-苯基-1,3,8-三氮杂螺[4.5]癸-4-酮(6)、1-[1-[3-[双(4-氟苯基)氨基]丙基]-4-哌啶基]-1,3-二氢-2H-苯并咪唑-2-酮(11)、1-[1-[3-[双(4-氟苯基)氨基]丙基]-1,2,3,6-四氢-4-吡啶基]-1,3-二氢-2H-苯并咪唑-2-酮(22)和1-[3-[双(4-氟苯基)氨基]丙基]-4-(2-甲氧基苯基)哌嗪(26)。
