3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.
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.
Atkinson
Peter J
PJ
Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Bromidge
Steven M
SM
Duxon
Mark S
MS
Gaster
Laramie M
LM
Hadley
Michael S
MS
Hammond
Beverley
B
Johnson
Christopher N
CN
Middlemiss
Derek N
DN
North
Stephanie E
SE
Price
Gary W
GW
Rami
Harshad K
HK
Riley
Graham J
GJ
Scott
Claire M
CM
Shaw
Tracey E
TE
Starr
Kathryn R
KR
Stemp
Geoffrey
G
Thewlis
Kevin M
KM
Thomas
David R
DR
Thompson
Mervyn
M
Vong
Antonio K K
AK
Watson
Jeannette M
JM
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
D048588:Benzoxazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors