title: Optimization of (arylpiperazinylbutyl)oxindoles exhibiting selective 5-HT₇ receptor antagonist activity.
abstract: A series of (arylpiperazinylbutyl)oxindoles as highly potent 5-HT(7) receptor antagonists has been studied for their selectivity toward the 5-HT(1A) receptor and α(1)-adrenoceptor. Several derivatives exhibited high 5-HT(7)/5-HT(1A) selectivity, and the key structural factors for reducing undesired α(1)-adrenergic receptor binding have also been identified. Rapid metabolism, a common problem within this family of compounds, could be circumvented with appropriate substitution patterns on the oxindole carbocycle. Contrary to expectations, none of the compounds produced an antidepressant-like action in the forced swimming test in mice despite sufficiently high brain concentrations. On the other hand, certain analogues showed significant anxiolytic activity in two different animal models: the Vogel conflict drinking test in rats and the light-dark test in mice.
authors.affiliation: Chemical Research Division, EGIS Pharmaceuticals Plc., P.O. Box 100, Budapest, H-1475 Hungary. volk.balazs@egis.hu
authors.forename: Balázs
authors.initials: B
authors.lastname: Volk
authors.forename: István
authors.initials: I
authors.lastname: Gacsályi
authors.forename: Katalin
authors.initials: K
authors.lastname: Pallagi
authors.forename: László
authors.initials: L
authors.lastname: Poszávácz
authors.forename: Ildikó
authors.initials: I
authors.lastname: Gyönös
authors.forename: Eva
authors.initials: E
authors.lastname: Szabó
authors.forename: Tibor
authors.initials: T
authors.lastname: Bakó
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
authors.forename: Gyula
authors.initials: G
authors.lastname: Simig
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
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; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A