SIGMA-LIGANDS WITH SUBNANOMOLAR AFFINITY AND PREFERENCE FOR THE SIGMA(2) BINDING-SITE .1. 3-(OMEGA-AMINOALKYL)-1H-INDOLES

A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4-phenyl-1,2,3,6-tetra-hydropyridines, and 4-phenylpiperazines was sy nthesized. The phenyl group was optionally substituted with 4-fluoro o r 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 D-2, and adrenergic alpha(1) receptors. Introduction of a 4 -fluorophenyl substituent at the indole nitrogen atom rendered very se lective sigma(2) ligands with subnanomolar affinity for the sigma(2) b inding site. The prototype of such a compound was 4-fluorophenyl)-1-pi peridinyl]-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 (D)(2) = 4200 nM, IC50 (alpha(1))= 220 nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-pi peridine] ring system resulted in even more selective compounds. Varia tions of the l-substituent at the indole and of the chain length of th e alkylene spacer group were;studied. The optimal compound was the spi ro analogue of compound 11a. This compound is 1'-[4-[1-(4-fluorophenyl )- -1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine], 14f(code no. Lu 28-179), with the binding affinities: IC50(sigma(1)) = 17 nM, IC50 (si gma(2)) = 0.12 nM, IC50 (5-HT1A) = 21 000 nM, IC50 (5-HT2A) = 2000 nM, IC50 (D-2)= 800 nM, IC50 (alpha(1))= 330 nM. However, the most select ive sigma(2) versus sigma(1) ligand was the tropane derivative zabicyc lo[3.2.l]oct-2-en-8-yl]-1-butyl]-1H-indole, 15a. This compound had the following binding affinitites: IC50 (sigma(1)) = 1200 nM, IC50 (sigma (2)) = 2.5 nM. Potent anxiolytic activity in the black/white box explo ration test in rats was found with the two most prominent sigma(2) lig ands Lu 29-253 and Lu 28-179. Good penetration into the CNS was docume nted both after subcutaneous and peroral administration of Lu 28-179 b y ex vivo binding studies. Long duration of action was demonstrated bo th in ex vivo binding (T-1/2 similar to 20 h) and in the black/white b ox exploration test.