title: Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents.
abstract: A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized and evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT1A, 5-HT7and mixed 5-HT1A/5-HT7receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.
authors.affiliation: a Department of Medicinal Chemistry.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagórska
authors.affiliation: a Department of Medicinal Chemistry.
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: a Department of Medicinal Chemistry.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: b Department of Pharmacobiology.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: c Department of Pharmacodynamics.
authors.forename: Monika
authors.initials: M
authors.lastname: Głuch-Lutwin
authors.affiliation: c Department of Pharmacodynamics.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Starowicz
authors.affiliation: c Department of Pharmacodynamics.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kazek
authors.affiliation: d Department of Clinical Pharmacy , and.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: d Department of Clinical Pharmacy , and.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.affiliation: e Department of Pharmaceutical Biochemistry , Jagiellonian University Medical College , Kraków , Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Słoczyńska
authors.affiliation: e Department of Pharmaceutical Biochemistry , Jagiellonian University Medical College , Kraków , Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: a Department of Medicinal Chemistry.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D020374:Chromatography, Micellar Electrokinetic Capillary; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011688:Purinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: C000614227:1H-imidazo(2,1-f)purine-2,4(3H,8H)-dione; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D007093:Imidazoles; D011688:Purinones; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human
keywords: Depression; PDE; long-chain arylpiperazines; phosphodiesterase inhibitors; serotonin