title: Structure-activity relationship studies of CNS agents. Part 38. Novel 1,4-benzoxazin-3(4H)-one, 1,2-benzoxazolin-3-one and 1,3-benzoxazolin-2,4-dione arylpiperazine derivatives with different 5-HT1A and antagonistic 5-HT2A activities.
abstract: New 1-arylpiperazine (series d-f) and 1,2,3,4-tetrahydroisoquinoline (series g) derivatives of 1,4-benzoxazin-3(4H)-one 1, 1,2-benzoxazolin-3-one 2, and 1,3-benzoxazolin-2,4-dione 3 with an n-butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5-HT1A and 5-HT2A receptors in comparison with trimethylene analogues (a, bc). 5-HT1A receptor binding constants of derivatives 1d-g, 2d-f, and 3d-f were very high (Ki = 1.25-54 nM), and 5-HT2A affinities were maintained at a similar, high level (Ki = 27-85 nM) for series d and e, and moderate (Ki = 246-495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5-HT1A/5-HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5-HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5-HT2A binding constants in comparison with trimethylene analogues. As shown by X-ray crystallography, this phenomenon may be attributed to the position of non-carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e-g, 2d-f, and 3f behaved like typical postsynaptic 5-HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5-HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5-HT1A antagonist.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology PAS, Kraków, Poland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mokrosz
authors.forename: P
authors.initials: P
authors.lastname: Kowalski
authors.forename: T
authors.initials: T
authors.lastname: Kowalska
authors.forename: Z
authors.initials: Z
authors.lastname: Majka
authors.forename: B
authors.initials: B
authors.lastname: Duszyńska
authors.forename: A J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: A
authors.initials: A
authors.lastname: Fruziński
authors.forename: J
authors.initials: J
authors.lastname: Karolak-Wojciechowska
authors.forename: A
authors.initials: A
authors.lastname: Wesołowska
authors.forename: A
authors.initials: A
authors.lastname: Kłodzińska
authors.forename: E
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: E
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists