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[摘要]：The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity alpha(1A)-adrenoceptor ligands with K-i values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D-2 receptors. Compound 3i showed almost equal affinity for alpha(1B)- (K-i = 1.9 nM) and alpha(1D)-adrenoceptors (K-i = 2.5 nM) as for alpha(1A), as well as moderate affinity for 5-HT1B (K-i = 13 nM) and 5-HT6 (K-i = 16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands. (C) 2012 Elsevier Ltd. All rights reserved. |
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