σ Ligands with subnanomolar affinity and preference for the σ2 binding site. 1. 3-(ω-Aminoalkyl)-1H-indoles

Article abstract of DOI:10.1021/jm00011a019

A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines, 4- phenyl-1,2,3,6-terrahydropyridines, and 4-phenylpiperazines was synthesized. The phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents. High affinity for both σ₁ and σ₁ binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT(1A) and 5-HT(2A), dopamine D₂, and adrenergic α₁ receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective σ₂ ligands with subnanomolar affinity for the σ₂ 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 (σ₁) = 16 nM, IC₅₀ (σ₂) = 0.27 riM, IC₅₀ (5-HT(1A)) = 22 000 nM, IC₅₀ (5-HT(2A)) = 270 nM, IC₅₀ (D₂) = 4200 nM, IC₅₀ (α₁) = 220nM. Spiro-joining of the phenyl and the piperidine rings into a spiro[isobenzofuran-1(3H),4'-piperidinel 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'-14-[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 (σ₁) = 17 nM, IC₅₀ (σ₂) = 0.12 nM, IC₅₀ (5-HT(1A)) = 21 000 nM, IC₅₀ (5-HT(2A)) = 2000 nM, IC₅₀ (D₂) = 800 nM, IC₅₀ (α₁) = 330 nM. However, the most selective σ₂ versus σ₁ 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 (σ₁) = 1200 nM, IC₅₀ (σ₂) = 2.5 nM. Potent anxiolytic activity in the black/white box exploration test in rats was found with the two most prominent σ₂ 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 (T(1/2) ~ 20 h) and in the black/white box exploration test.