RT Journal Article
T1 Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs
A1 Kondej, Magda
A1 Silva, Andrea G.
A1 Loza García, María Isabel
A1 Castro Pérez, María de los Ángeles
A1 Kaczor, Agnieszka A.
AB Schizophrenia is a complex disease with not fully understood pathomechanism, involving many neurotransmitters and their receptors. This is why it is best treated with multi-target drugs, such as second generation antipsychotics. Here we present 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles (1-20) which are ligands of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors and display affinity in the nanomolar range. These compounds were designed as modifications of the virtual hit experimentally confirmed, D2AAK1, and synthesized from indole or 5-alkoxyindoles and N-substituted piperidin-4-ones in methanol in the presence of potassium hydroxide. Compound 9 was subjected to X-ray studies and it crystallizes in the centrosymmetric monoclinic space group P21/c with one molecule in an asymmetric unit. Three most potent compounds (5, 9 and 17) turned out to be antagonists of both D2 and 5-HT2A receptors what is beneficial for their potential application as antipsychotics. Compound 5 was subjected to behavioral studies and exhibited antipsychotic, pro-cognitive and antidepressant activity in appropriate mice models. Structure-activity relationships for compounds 1-20 were rationalized using molecular docking. It was found that, in general, bulky C5-alkoxy substituents at the indole moiety are not favorable as they direct towards aqueous environment of the extracellular vestibule. Keywords: antipsychotics; behavioral studies, G protein-coupled receptors; indole derivatives; multi-target compounds; schizophrenia.
PB Elsevier Masson SAS
SN 0223-5234
YR 2019
FD 2019-07-20
LK https://hdl.handle.net/10347/39499
UL https://hdl.handle.net/10347/39499
LA eng
NO Kondej M, Wróbel TM, Silva AG, Stępnicki P, Koszła O, Kędzierska E, Bartyzel A, Biała G, Matosiuk D, Loza MI, Castro M, Kaczor AA. Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs. Eur J Med Chem. 2019 Oct 15;180:673-689
DS Minerva
RD 27 abr 2026