Perregaard J, Moltzen E K, Meier E, Sánchez C
H. Lundbeck A/S, Ottiliavej 9, Copenhagen-Valby, Denmark.
J Med Chem. 1995 May 26;38(11):1998-2008. doi: 10.1021/jm00011a019.
A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4-phenyl-1,2,3,6-tetrahydropyridines, and 4-phenylpiperazines was synthesized. The phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents. High affinity for both sigma 1 and sigma 2 binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT1A and 5-HT2A, dopamine D2, and adrenergic alpha 1 receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective sigma 2 ligands with subnanomolar affinity for the sigma 2 binding site. The prototype of such a compound was 1-(4-fluorophenyl)-3-[4-[4-(4-fluorophenyl)-1-piperidinyl]-1-butyl]-1H- indole, 11a (code no. Lu 29-253). This compound had the following binding affinities: IC50 (sigma 1) = 16 nM, IC50 (sigma 2) = 0.27 nM, IC50 (5-HT1A) = 22,000 nM, IC50 (5-HT2A) = 270 nM, IC50 (D2) = 4200 nM, IC50 (alpha 1) = 220 nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-piperdine] ring system resulted in even more selective compounds. Variations of the 1-substituent at the indole and of the chain length of the alkylene spacer group were studied. The optimal compound was the spiro analogue of compound 11a. This compound is 1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran- 1(3H),4'-piperidine], 14f (code no. Lu 28-179), with the binding affinities: IC50 (sigma 1) = 17 nM, IC50 (sigma 2) = 0.12 nM, IC50 (5-HT1A) = 21,000 nM, IC50 (5-HT2A) = 2000 nM, IC50 (D2) = 800 nM, IC50 (alpha 1) = 330 nM. However, the most selective sigma 2 versus sigma 1 ligand was the tropane derivative 1-(4-fluorophenyl)-3-[4-[3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2- en-8-yl]-1-butyl]-1H-indole, 15a. This compound had the following binding affinities: IC50 (sigma 1) = 1200 nM, IC50 (sigma 2) = 2.5 nM. Potent anxiolytic activity in the black/white box exploration test in rats was found with the two most prominent sigma 2 ligands Lu 29-253 and Lu 28-179. Good penetration into the CNS was documented both after subcutaneous and peroral administration of Lu 28-179 by ex vivo binding studies. Long duration of action was demonstrated both in ex vivo binding (T1/2 approximately 20 h) and in the black/white box exploration test.
合成了一系列4-(1H-吲哚-3-基)-1-丁基取代的4-苯基哌啶、4-苯基-1,2,3,6-四氢吡啶和4-苯基哌嗪。苯基可任选被4-氟或2-甲氧基取代基取代。这些化合物对σ1和σ2结合位点均具有高亲和力。此外，这些化合物对5-羟色胺5-HT1A和5-HT2A、多巴胺D2以及肾上腺素α1受体具有相对较高的亲和力。在吲哚氮原子处引入4-氟苯基取代基得到了对σ2结合位点具有亚纳摩尔亲和力的高选择性σ2配体。此类化合物的原型是1-(4-氟苯基)-3-[4-[4-(4-氟苯基)-1-哌啶基]-1-丁基]-1H-吲哚，即化合物11a（编号Lu 29-253）。该化合物具有以下结合亲和力：IC50(σ1)=16 nM，IC50(σ2)=0.27 nM，IC50(5-HT1A)=22000 nM，IC50(5-HT2A)=270 nM，IC50(D2)=4200 nM，IC50(α1)=220 nM。将苯基和哌啶环螺合形成螺[异苯并呋喃-1(3H),4'-哌啶]环系得到了选择性更高的化合物。研究了吲哚上1-取代基和亚烷基间隔基团链长的变化。最佳化合物是化合物11a的螺环类似物。该化合物是1'-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]螺[异苯并呋喃-1(3H),4'-哌啶]，即化合物14f（编号Lu 28-179），其结合亲和力为：IC50(σ1)=17 nM，IC50(σ2)=0.12 nM，IC50(5-HT1A)=21000 nM，IC50(5-HT2A)=2000 nM，IC50(D2)=800 nM，IC50(α1)=330 nM。然而，对σ2与σ1选择性最高的配体是托烷衍生物1-(4-氟苯基)-3-[4-[3-(4-氟苯基)-8-氮杂双环[3.2.1]辛-2-烯-8-基]-1-丁基]-1H-吲哚，即化合物15a。该化合物具有以下结合亲和力：IC50(σ1)=1200 nM，IC50(σ2)=2.5 nM。在大鼠黑白箱探索试验中，两种最突出的σ2配体Lu 29-253和Lu 28-179表现出强效抗焦虑活性。通过体外结合研究证明，皮下和口服给予Lu 28-179后均具有良好的中枢神经系统渗透性。在体外结合试验（半衰期约为20小时）和黑白箱探索试验中均证明了其作用持续时间长。
