title: 5-HT2 receptor affinity, docking studies and pharmacological evaluation of a series of 1,3-disubstituted thiourea derivatives.
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.
authors.affiliation: Chair and Department of Biochemistry, Medical University of Warsaw, 02-097, Warszawa, Poland. Electronic address: abielenica@wum.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Bielenica
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 20-031, Lublin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kędzierska
authors.affiliation: Bioinformatics Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106, Warszawa, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Koliński
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093, Warszawa, Poland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kmiecik
authors.affiliation: Faculty of Chemistry, University of Warsaw, 02-093, Warszawa, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Koliński
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Fiorino
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Severino
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Magli
authors.affiliation: Dipartimento di Farmacia Università di Napoli "Federico II", Via D. Montesano, 49, 80131, Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corvino
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze Strada delle Scotte, Università di Siena, 6 53100, Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rossi
authors.affiliation: Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze Strada delle Scotte, Università di Siena, 6 53100, Siena, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Massarelli
authors.affiliation: Faculty of Chemistry, Maria Curie-Sklodowska University, 20-031, Lublin, Poland.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Kozioł
authors.affiliation: Faculty of Chemistry, Maria Curie-Sklodowska University, 20-031, Lublin, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Sawczenko
authors.affiliation: Department of Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097, Warszawa, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Struga
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000378:metabolism*; D013890:Thiourea / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D044405:Receptor, Serotonin, 5-HT2C; D013890:Thiourea
keywords: 5-HT(2A) receptor ligands; 5-HT(2C) receptor ligands; CNS activity; Docking studies; Thiourea