Perregaard J, Arnt J, Bøgesø K P, Hyttel J, Sánchez C
Research Department, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
J Med Chem. 1992 Mar 20;35(6):1092-101. doi: 10.1021/jm00084a014.
A series of 1-(4-fluorophenyl)-1H-indoles substituted at the 3-position with 1-piperazinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperidinyl was synthesized. Within all three subseries potent dopamine D-2 and serotonin 5-HT2 receptor affinity was found in ligand binding studies. Quipazine-induced head twitches in rats were inhibited by most derivatives as a measure of central 5-HT2 receptor antagonism. Piperazinyl and tetrahydropyridyl indoles were cataleptogenic, while piperidyl substituted indoles surprisingly were found to be noncataleptogenic or only weakly cataleptogenic. Noncataleptogenic piperidyl derivatives also failed to block dopaminergic-mediated stereotypies, that is methyl phenidate-induced gnawing behavior in mice. These profiles resemble that of the atypical neuroleptic clozapine. 1-Ethyl-2-imidazolidinone was found to be the optimal substituent of the basic nitrogen atom in order to avoid catalepsy. The atypical neuroleptic 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl] ethyl]-2-imidazolidinone (sertindole, compound 14c) was selected for further development as a result of these structure/activity studies.
合成了一系列在3-位被1-哌嗪基、1,2,3,6-四氢-4-吡啶基和4-哌啶基取代的1-(4-氟苯基)-1H-吲哚。在所有三个子系列中，配体结合研究发现其对多巴胺D-2和5-羟色胺5-HT2受体具有强效亲和力。作为中枢5-HT2受体拮抗作用的一种衡量方法，大多数衍生物可抑制大鼠中喹哌嗪诱导的头部抽搐。哌嗪基和四氢吡啶基吲哚具有致僵作用，而令人惊讶的是，哌啶基取代的吲哚被发现无致僵作用或仅有微弱的致僵作用。无致僵作用的哌啶基衍生物也无法阻断多巴胺能介导的刻板行为，即小鼠中哌醋甲酯诱导的啃咬行为。这些特征与非典型抗精神病药物氯氮平的特征相似。为了避免僵住症，发现1-乙基-2-咪唑烷酮是碱性氮原子的最佳取代基。基于这些构效关系研究，选择了非典型抗精神病药物1-[2-[4-[5-氯-1-(4-氟苯基)-1H-吲哚-3-基]-1-哌啶基]乙基]-2-咪唑烷酮（舍吲哚，化合物14c）进行进一步研发。
