title: New arylpiperazinylalkyl derivatives of 8-alkoxy-purine-2,6-dione and dihydro[1,3]oxazolo[2,3-f]purinedione targeting the serotonin 5-HT1A /5-HT2A /5-HT7 and dopamine D2 receptors.
abstract: To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 ) and dopamine (D2 ) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A /5-HT7 /D2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Chłoń-Rzepa
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagórska
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.forename: Karolina
authors.initials: K
authors.lastname: Słoczyńska
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001711:Biotransformation; D065127:Dopamine D2 Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D011687:Purines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D011687:Purines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A
keywords: Arylpiperazines; Depression; Serotonin receptor ligands