title: 3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.
abstract: Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
authors.affiliation: Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Atkinson
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: Mark S
authors.initials: MS
authors.lastname: Duxon
authors.forename: Laramie M
authors.initials: LM
authors.lastname: Gaster
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hadley
authors.forename: Beverley
authors.initials: B
authors.lastname: Hammond
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Derek N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: North
authors.forename: Gary W
authors.initials: GW
authors.lastname: Price
authors.forename: Harshad K
authors.initials: HK
authors.lastname: Rami
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Riley
authors.forename: Claire M
authors.initials: CM
authors.lastname: Scott
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Shaw
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Starr
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Thewlis
authors.forename: David R
authors.initials: DR
authors.lastname: Thomas
authors.forename: Mervyn
authors.initials: M
authors.lastname: Thompson
authors.forename: Antonio K K
authors.initials: AK
authors.lastname: Vong
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004355:Drug Stability; D006801:Humans; D011869:Radioligand Assay; D051381:Rats; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors