期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 18, 页码 6195-6209出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.07.050
关键词
3D-QSAR; D-2 partial agonist; CoMFA; CoMSIA; GPCR; Subtype selectivity; 5-HT2A/D-2 selectivity; Dopamine receptor; Serotonin receptor; Phenylpiperazine; 1,4-DAP
资金
- German Science Foundation (DFG) [GRK 1910]
- DAAD
Simultaneous targeting of dopamine D-2 and 5-HT2A receptors for the treatment of schizophrenia is one key feature of typical and atypical antipsychotics. In most of the top-selling antipsychotic drugs like aripiprazole and risperidone, high affinity to both receptors can be attributed to the presence of 1,4-disubstituted aromatic piperazines or piperidines as primary receptor recognition elements. Taking advantage of our in-house library of phenylpiperazine-derived dopamine receptor ligands and experimental data, we established highly significant CoMFA and CoMSIA models for the prediction of 5-HT2A over D-2 selectivity. Subsequently, the models were applied to identify the selective candidates 55-57 from our newly synthesized library of GPCR ligands comprising a pyrazolo[1,5-a]pyridine head group and a 1,2,3-triazole based linker unit. The test compound 57 showed subnanomolar a K-i value (0.64 nM) for 5-HT2A and more than 10- and 30-fold selectivity over the dopamine receptor isoforms D-2S and D-2L, respectively. (c) 2015 Elsevier Ltd. All rights reserved.
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