title: Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor.
abstract: The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.
authors.affiliation: Department of Medicinal Chemistry, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: M D
authors.initials: MD
authors.lastname: Ennis
authors.forename: M E
authors.initials: ME
authors.lastname: Baze
authors.forename: M W
authors.initials: MW
authors.lastname: Smith
authors.forename: C F
authors.initials: CF
authors.lastname: Lawson
authors.forename: R B
authors.initials: RB
authors.lastname: McCall
authors.forename: R A
authors.initials: RA
authors.lastname: Lahti
authors.forename: M F
authors.initials: MF
authors.lastname: Piercey
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002415:Cats; D004146:Dioxanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011869:Radioligand Assay; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D004146:Dioxanes; D007211:Indoles; D008024:Ligands; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid; D011985:Receptors, Serotonin