Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties.
Eur J Med Chem
; 185: 111857, 2020 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-31734022
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 Kiâ¯=â¯91â¯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 Kiâ¯=â¯25, 5-HT2AR Kiâ¯=â¯32â¯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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antipsicóticos
/
Triptaminas
/
Receptores de Serotonina
/
Cognición
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Receptor de Serotonina 5-HT2A
/
Antidepresivos
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article