3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity

Peter J Atkinson; Steven M Bromidge; Mark S Duxon; Laramie M Gaster; Michael S Hadley; Beverley Hammond; Christopher N Johnson; Derek N Middlemiss; Stephanie E North; Gary W Price; Harshad K Rami; Graham J Riley; Claire M Scott; Tracey E Shaw; Kathryn R Starr; Geoffrey Stemp; Kevin M Thewlis; David R Thomas; Mervyn Thompson; Antonio K K Vong; Jeannette M Watson

doi:10.1016/j.bmcl.2004.11.030

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity

Bioorg Med Chem Lett. 2005 Feb 1;15(3):737-41. doi: 10.1016/j.bmcl.2004.11.030.

Affiliation

¹ Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

PMID: 15664848
DOI: 10.1016/j.bmcl.2004.11.030

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.

MeSH terms

Animals
Benzoxazines / chemical synthesis*
Benzoxazines / pharmacology
Biological Availability
Brain / metabolism
Cell Line
Drug Stability
Humans
Radioligand Assay
Rats
Selective Serotonin Reuptake Inhibitors / chemical synthesis*
Selective Serotonin Reuptake Inhibitors / pharmacology
Serotonin 5-HT1 Receptor Antagonists*
Structure-Activity Relationship
Synaptosomes / metabolism

Substances

Benzoxazines
Serotonin 5-HT1 Receptor Antagonists
Serotonin Uptake Inhibitors