title: Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity.
abstract: A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and D2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D2 ligands. The most interesting because of their multireceptor profile were 8-piperidine (30-35) and 8-dipropylamine (45-47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT1A and D2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing d-amphetamine-induced hyperactivity in mice.
authors.affiliation: a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland .
authors.forename: Grażyna
authors.initials: G
authors.lastname: Chłoń-Rzepa
authors.affiliation: a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland .
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland .
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: b Department of Clinical Pharmacy , Jagiellonian University Medical College , Kraków , Poland .
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: b Department of Clinical Pharmacy , Jagiellonian University Medical College , Kraków , Poland .
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.affiliation: c Department of Medicinal Chemistry , Institute of Pharmacology, Polish Academy of Sciences , Kraków , Poland .
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: c Department of Medicinal Chemistry , Institute of Pharmacology, Polish Academy of Sciences , Kraków , Poland .
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: d Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry , Jagiellonian University , Kraków , Poland .
authors.forename: Justyna
authors.initials: J
authors.lastname: Kalinowska-Tłuścik
authors.affiliation: e Department of Pharmacological Screening , Jagiellonian University Medical College , Kraków , Poland , and.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: f Department of Pharmacobiology , Jagiellonian University Medical College , Kraków , Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mordyl
authors.affiliation: f Department of Pharmacobiology , Jagiellonian University Medical College , Kraków , Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Głuch-Lutwin
authors.affiliation: b Department of Clinical Pharmacy , Jagiellonian University Medical College , Kraków , Poland .
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D002853:Chromatography, Liquid; D010879:Piperazines / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D011687:Purines / Q000737:chemistry*; D011985:Receptors, Serotonin / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D011687:Purines; D011985:Receptors, Serotonin
keywords: Antipsychotics; D2 partial agonist; arylpiperazines; derotonin receptor ligands