title: 1,4-Benzoxazin-3(4H)-one derivatives and related compounds as 5-HT1A and 5-HT2A receptor ligands; the effect of the terminal amide fragment on the 5-HT1A/5-HT2A affinity and functional activity.
abstract: A number of new 1-phenyl- (a), 1-(3-chlorophenyl)- (b) and 1-(2-methoxyphenyl)- (c) piperazine derivatives containing 1,4-benzoxazin-3(4H)-one (2-4), 2,4-benzoxazin-3-(4H)-one (5), 1,2-benzoxazolin-3-one (6) and 1,3-benzoxazolin-2,4-dione (7) were synthesized. Radioligand binding measurements showed that the majority of compounds had a distinct affinity for 5-HT1A (3a, 6a, 2-5b, 6c; Ki = 7.5-81 nM) and/or 5-HT2A (2b, 5-7a,b; Ki = 18-69 nM) receptors. Structure-Activity Relationship (SAR) studies revealed structural features which seem to favour the binding to either or both of these two receptor subtypes. For evaluation of the functional in vivo profile of the most potent 5-HT1A (5b, 6b) and/or 5-HT2A (5-7b) ligands, the following tests were used: the 8-OH-DPAT-induced lower lip retraction (LLR) and behavioral syndrome in rats--for 5-HT1A receptor antagonistic activity, and the (+/-)DOI-induced head twitches in mice and the (+/-)DOI-induced discriminative stimulus properties in rats--for 5-HT2A receptor antagonistic properties. The obtained results show that compounds 5b and 6c behave like potent 5-HT1A antagonists, whereas 5b, 6b and 7b demonstrate 5-HT2A receptor antagonistic properties. None of the in vivo tested compounds, given alone, mimicked 8-OH-DPAT activity in those tests. It seems that derivative 5b, which has an equipotent 5-HT1A and 5-HT2A affinity and antagonistic properties at both these receptors, is a promising potential psychotropic substance.
authors: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
authors: M J
authors: MJ
authors: Mokrosz
authors: P
authors: P
authors: Kowalski
authors: T
authors: T
authors: Kowalska
authors: Z
authors: Z
authors: Majka
authors: B
authors: B
authors: Duszyńska
authors: S
authors: S
authors: Charakchieva-Minol
authors: A
authors: A
authors: Szaro
authors: E
authors: E
authors: Tatarczyńska
authors: A
authors: A
authors: Kłodzińska
authors: E
authors: E
authors: Chojnacka-Wójcik
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004347:Drug Interactions; D019416:Head Movements / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008046:Lip / Q000187:drug effects; D008297:Male; D051379:Mice; D009128:Muscle Spasticity / Q000139:chemically induced; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012110:Reserpine / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010078:Oxazines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine