147372-95-0Relevant academic research and scientific papers
Sigma-2 receptor agonists as possible antitumor agents in resistant tumors: Hints for collateral sensitivity
Niso, Mauro,Abate, Carmen,Contino, Marialessandra,Ferorelli, Savina,Azzariti, Amalia,Perrone, Roberto,Colabufo, Nicola Antonio,Berardi, Francesco
, p. 2026 - 2035 (2014/01/06)
With the aim of contributing to the development of novel antitumor agents, high-affinity σ2 receptor agonists were developed, with 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3, 4-tetrahydroisoquinoline (15) and 9-[4-(6,7-di
Substituted benzylaminoalkylindoles with preference for the σ2 binding site
Mamolo, Maria Grazia,Zampieri, Daniele,Zanette, Caterina,Florio, Chiara,Collina, Simona,Urbano, Mariangela,Azzolina, Ornella,Vio, Luciano
, p. 2073 - 2081 (2008/12/23)
In the attempt to develop new σ ligands we synthesized a series of N-benzyl-3-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylpropan-1-amines and N-benzyl-4-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylbutan-1-amines variously substituted on the phenyl ring. The displacement percentages of [3H]-DTG and [3H]-(+)-pentazocine determined in rat liver homogenates by these compounds at the fixed 100 nM concentration have been determined as a preliminary evaluation of their σ1 and σ2 affinity, respectively. The results suggested that the phenyl substituents may positively modulate, in comparison with the unsubstituted compound, the ability to displace [3H]-DTG from σ2 sites, whereas the same phenyl substituents reduced the displacement percentages of [3H]-(+)-pentazocine from σ1 sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for σ2 over σ1 receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest σ2 affinity (σ2Ki = 5.9 nM) and an appreciable σ2 over σ1 selectivity (σ1Ki/σ2Ki = 22). The obtained results suggest that a butylene chain separating the indole moiety from variously substituted benzylamino groups may be required to their interaction with a hypothetical secondary σ2 binding site.
N-Arylation of indoles with 4-[18F]fluoroiodobenzene: Synthesis of 18F-labelled σ2 receptor ligands for positron emission tomography (PET)
Wuest, Frank R.,Kniess, Torsten
, p. 31 - 43 (2007/10/03)
The palladium-mediated N-arylation of indoles with 4-[18F] fluoroiodobenzene as a novel radiolabelling method has been developed. Optimized reaction conditions were elaborated by variation of different catalyst systems (CuI/1,2-diamines and Pd2
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.
