title: Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT₁A receptor functional profile.
abstract: Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4-14) and 7-tetrahydroisoquinolinyl-alkyl (15-17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant- and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam.
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: mfpartyk@cyf-kr.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: mfchlon@cyf-kr.edu.pl.
authors.forename: Grażyna
authors.initials: G
authors.lastname: Chłoń-Rzepa
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: annawasik87@gmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Wasik
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: m.jastrzebska-wiesek@uj.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: adam.bucki@uj.edu.pl.
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: marcin.kolaczkowski@uj.edu.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland. Electronic address: satala@if-pan.krakow.pl.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland. Electronic address: bojarski@if-pan.krakow.pl.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: awesolowska@cm-uj.krakow.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000494:pharmacology; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D051379:Mice; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D011687:Purines; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT(1A) receptor agonist/antagonist; 5-HT(2A) receptor antagonist; 5-HT(7) receptor antagonist; Anxiety; Depression; Long-chain arylpiperazines; Purine-2,6-diones