title: Aminoalkyl Derivatives of 8-Alkoxypurine-2,6-diones: Multifunctional 5-HT1A/5-HT7Receptor Ligands and PDE Inhibitors with Antidepressant Activity.
abstract: In the search for potential psychotropic agents, a new series of 3,7-dimethyl- and 1,3-dimethyl-8-alkoxypurine-2,6-dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5-16 and 21-32) were synthesized and evaluated for 5-HT1A/5-HT7receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-3,7-dimethyl-8-propoxypurine-2,6-dione (16) and 7-(2-hydroxyphenyl)piperazinylalkyl-1,3-dimethyl-8-ethoxypurine-2,6-diones (31 and 32) as potent dual 5-HT1A/5-HT7receptor ligands with antagonistic activity produced an antidepressant-like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10-5M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5-HT1and 5-HT7receptors, especially in the case of compounds 15 and 16. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Chłoń-Rzepa
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagórska
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Żmudzki
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.affiliation: Department of Pharmacological Screening, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: Department of Pharmacological Screening, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Głuch-Lutwin
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Starowicz
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects; D046353:Immobility Response, Tonic / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013805:Theobromine / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D007527:Isoenzymes; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D013806:Theophylline; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse; D013805:Theobromine
keywords: Depression; PDE inhibitors; Serotonin receptor ligands