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.

Bielenica, A., Kȩdzierska, E., Koliński, M., Kmiecik, S., Koliński, A., Fiorino, F., et al. (2016). 5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 116, 173-186 [10.1016/j.ejmech.2016.03.073].

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

MASSARELLI, PAOLA;
2016-01-01

Abstract

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.
2016
Bielenica, A., Kȩdzierska, E., Koliński, M., Kmiecik, S., Koliński, A., Fiorino, F., et al. (2016). 5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 116, 173-186 [10.1016/j.ejmech.2016.03.073].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1004705