Discovery of novel alpha(1)-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands.
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Jorgensen M, Jorgensen PN, Christoffersen CT, Jensen KG, Balle T, Bang-Andersen B
Discovery of novel alpha(1)-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands.
Bioorg Med Chem. 2013 Jan 1;21(1):196-204. doi: 10.1016/j.bmc.2012.10.049. Epub 2012 Nov 15.
- PubMed ID
- 23218776 [ View in PubMed]
- Abstract
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-HT(1B) (K(i)=13 nM) and 5-HT(6) (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.
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Sertindole Dopamine D2 receptor Ki (nM) 0.45 N/A N/A Details