Rationally designed N-phenylsulfonylindoles as a tool for the analysis of the non-basic 5-HT 6 R ligands binding mode.

Autor: Staroń J; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland. Electronic address: staron@if-pan.krakow.pl., Bugno R; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Pietruś W; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Satała G; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Mordalski S; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Warszycki D; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Hogendorf A; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Hogendorf AS; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Kalinowska-Tłuścik J; Department of Crystal Chemistry and Crystal Physic Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland., Lenda T; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland., Pilarski B; CERKO, 96/98 Zwycięstwa Avenue, 81-525, Gdynia, Poland., Bojarski AJ; Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, 12 Smętna Street, Poland.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Jan 01; Vol. 209, pp. 112916. Date of Electronic Publication: 2020 Oct 09.
DOI: 10.1016/j.ejmech.2020.112916
Abstrakt: Among all of the monoaminergic receptors, the 5-HT 6 R has the highest number of non-basic ligands (approximately 5% of compounds stored in 25th version of ChEMBL database have the strongest basic pKa below 5, calculated using the Instant JChem calculator plugin). These compounds, when devoid of a basic nitrogen, exhibit high affinity and remarkable selectivity. Despite a decade of research, no clues have been given for explanation of such an intriguing phenomenon. Here, a series of analogs of four known 5-HT 6 R ligands, has been rationally designed to approach this issue. For each of the synthesized 42 compounds, a binding affinity for 5-HT 6 R has been measured, together with a selectivity profile against 5-HT 1A R, 5-HT 2A R, 5-HT 7 R and D 2 R. Performed induced fit docking and molecular dynamics experiments revealed that no particular interaction was responsible for the activity of non-basic compounds. In fact, a plain N-phenylsulfonylindole (1e) was found to possess a moderate (5-HT 6 R, K i  = 159 nM) affinity. No other monoaminergic receptor has as simple and selective ligand as this one. Thus, it is stated that it binds to the receptor solely based on its conformation and as such, possesses a minimum amount of features, required for binding. Also, any functional group able to form an additional interaction with the receptor increase the binding affinity, like in the case of two highly active non-basic compounds 3e and 5g (5-HT 6 R, K i  = 65 nM and 38 nM, respectively).
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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