163630-95-3Relevant academic research and scientific papers
Piperidine derivatives having anxiolytic effect
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, (2008/06/13)
Piperidine compounds having the general formula (I), STR1 wherein R 1 is a group having general formula (II), STR2 wherein X is CHR 10, O, S, SO, SO 2 or NR 10, Z 1 is CH 2, O, or S; Z 2 and Z 3 are independently (CH 2) n, n being 0 or 1, O or S or Z 1 and Z 2 may together represent a group --CH CH--; or when Z 3 is (CH 2) n wherein n is 0, Z 1 and Z 2 may together represent a 3-membered divalent group; show potent sigma receptor activity. Furthermore they show effect in animal models indicative of anxiolytic properties. Accordingly they are useful as medicines for the treatment of anxiety, psychosis, epilepsy, convulsion, movement disorders, motor disturbances, amnesia, cerebrovascular diseases, senile demential of the Alzheimer type or Parkinson''s disease.
σ Ligands with subnanomolar affinity and preference for the σ2 binding site. 1. 3-(ω-Aminoalkyl)-1H-indoles
Perregaard,Moltzen,Meier,Sanchez
, p. 1998 - 2008 (2007/10/02)
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.
