5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives.

Title5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives.
Publication TypeJournal Article
Year of Publication2016
AuthorsBielenica, Anna, Kędzierska Ewa, Koliński Michał, Kmiecik Sebastian, Koliński Andrzej, Fiorino Ferdinando, Severino Beatrice, Magli Elisa, Corvino Angela, Rossi Ilaria, Massarelli Paola, Kozioł Anna E., Sawczenko Aleksandra, and Struga Marta
JournalEur J Med Chem
Volume116
Pagination173-186
Date Published2016 Mar 30
ISSN1768-3254
Abstract<p>A series of 10 thiourea derivatives have been synthesized by the reaction of aromatic amine with a substituted aryl (compounds 1-3, 6-8) and alkylphenyl (4, 5, 9, 10) isothiocyanates. Their in vitro and in vivo pharmacological properties were studied. Among the evaluated compounds, two displayed very high affinity for the 5-HT2A receptor (1-0.043 nM and 5-0.6 nM), being selective over the 5-HT2C receptor. Derivatives 3, 5, 9, 10 by 70-89% diminished L-5-HTP-induced head twitch episodes. Compounds 1 and 5 as the 5-HT2A receptor antagonists produced a dose-dependent decrease in the number of DOI-elicited HTR. Compounds 1-5 strongly reduced amphetamine-evoked hyperactivity in rodents. In another test, 1 and 2 caused hyperthermia in mice, whereas 9 and 10 led to hypothermia. Antinociceptive and anticonvulsant properties of selected derivatives were demonstrated. Molecular docking studies using a homology model of 5-HT2A revealed a significant role of hydrogen bonds between both thiourea NH groups and Asp155/Tyr370 residues, as well as π-π interaction with Phe339.</p>
DOI10.1016/j.ejmech.2016.03.073
Alternate JournalEur J Med Chem
PubMed ID27061981