Andersen K, Perregaard J, Arnt J, Nielsen J B, Begtrup M
H. Lundbeck A/S, Copenhagen-Valby, Denmark.
J Med Chem. 1992 Dec 25;35(26):4823-31. doi: 10.1021/jm00104a007.
A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).
合成了一系列在1位被4 - 哌啶基、1,2,3,6 - 四氢 - 4 - 吡啶基和4 - 哌嗪基取代的3 - (4 - 氟苯基)-1H - 吲哚。通过改变1 - [2 - [4 - [3 - (4 - 氟苯基)-1H - 吲哚 - 1 - 基]-1 - 哌啶基]-乙基]-2 - 咪唑啉酮中吲哚核苯部分的取代基，5 - 甲基取代获得了相对于多巴胺D2受体和α1肾上腺素能受体而言最高的5 - HT2受体亲和力和选择性。在5 - 甲基取代衍生物的哌啶环1位引入了不同的取代基。因此，用2 - (1,3 - 二甲基 - 1 - 脲基)乙基或甲基取代基取代2 - (2 - 咪唑啉酮 - 1 - 基)乙基侧链，导致对5 - HT2受体的亲和力和选择性不变。与3 - 未取代的咪唑啉酮相比，用2 - [3 - (2 - 丙基)-2 - 咪唑啉酮 - 1 - 基]乙基侧链取代使与α1肾上腺素能受体的结合降低了四倍，同时保留了对5 - HT2和D2受体的亲和力。与相应的4 - 哌啶基和1,2,3,6 - 四氢 - 4 - 吡啶基取代的吲哚相比，1位被4 - 哌嗪基取代的吲哚对5 - HT2和D2受体的亲和力通常较弱。在5 - 甲基取代吲哚的2位引入甲基导致对5 - HT2受体的选择性进一步增加。具有强效受体结合能力的化合物也能有效抑制大鼠中喹哌嗪诱导的头部抽搐综合征。这些化合物经口服和皮下给药后活性相同，且作用持续时间长(> 24小时)。一般来说，发现这些衍生物在给药后24小时比2小时时活性更强。该系列中的化合物是通过交换吲哚核中的C - 3碳原子和氮原子，作为先前描述的1 - (4 - 氟苯基)-3 - (4 - 哌啶基)-1H - 吲哚的类似物制备的。药理结果表明，这种等排取代相对于前一系列而言导致对5 - HT2受体具有更高的选择性。1 - [2 - [4 - [2,5 - 二甲基 - 3 - (4 - 氟苯基)-1H - 吲哚 - 1 - 基]-1 - 哌啶基]乙基]-2 - 咪唑啉酮对5 - HT2受体具有高亲和力(IC50 = 3.4 nM)，对多巴胺D2受体(IC50 = 6900 nM)和α1肾上腺素能受体(IC50 = 2300 nM)的亲和力极低。
