2. Academic Validation
  3. Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties

Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties

  • Eur J Med Chem. 2020 Jan 1;185:111857. doi: 10.1016/j.ejmech.2019.111857.
Jakub Staroń 1,  Rafał Kurczab 2,  Dawid Warszycki 2,  Grzegorz Satała 2,  Martyna Krawczyk 2,  Ryszard Bugno 2,  Tomasz Lenda 2,  Piotr Popik 2,  Adam S Hogendorf 2,  Agata Hogendorf 2,  Krzysztof Dubiel 3,  Mikołaj Matłoka 3,  Rafał Moszczyński-Pętkowski 3,  Jerzy Pieczykolan 3,  Maciej Wieczorek 3,  Paweł Zajdel 4,  Andrzej J Bojarski 2
Affiliations

Affiliations

  • 1 Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland. Electronic address: [email protected].
  • 2 Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland.
  • 3 Celon Pharma S.A., 2A Ogrodowa Street, 05-092, Łomianki, Poland.
  • 4 Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Kraków, Poland.
PMID: 31734022 DOI: 10.1016/j.ejmech.2019.111857
Abstract

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.

Keywords

5-HT2A; 5-HT6; CNS; Procognitive; Serotonin.

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