3,4-Dihydro-2H-benzoxazinones are 5-HT1A receptor antagonists with potent 5-HT reuptake inhibitory activity

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

“…In conclusion, SB-649915-B is a novel compound showing SSRI activity together with selective 5-HT 1A/B receptor blockade in a single molecule (Atkinson et al, 2005;Scott et al, 2006). The anxiolytic activity of this compound is shown in rodent and primate tests which also detect the activity of SSRIs after acute dosing.…”

“…In addition, 5-HT1 B/D antagonists augment an SSRI-induced increase in 5-HT (Dawson and Nguyen, 2000) and further potentiate the increase in 5-HT following WAY100635 and fluoxetine (Gobert et al, 2000). With this in mind, a novel 5-HT 1A/B autoreceptor antagonist and 5-HT reuptake inhibitor SB-649915-B has been developed (Atkinson et al, 2005). SB-649915-B occupies and fully blocks the serotonin transporter and 5-HT 1A/B receptors whilst inducing an increase in extracellular 5-HT , and mean % occupancy7SEM (n ¼ 3-4).…”

“…[ 3 H]citalopram binding and [ 3 H]5-HT uptake studies have also shown that SB-649915-B has high affinity for human recombinant and rat native SERT (Scott et al, 2006). SB-649915-B also has a good selectivity profile against other 5-HT, dopamine, and adrenergic (a 1B and b 2 ) receptors (Atkinson et al, 2005;Scott et al, 2006). In vivo SB-649915-B shows antagonism at 5-HT 1A and 5-HT 1B receptors as determined by the dose-dependent inhibition of 8-OH-DPAT-induced hyperlocomotion and SKF-99101-H-induced increase in seizure threshold (Hughes et al, 2007) respectively.…”

“…We report here the behavioral assessment of SB-649915-B, a novel SSRI and 5-HT 1A/B autoreceptor antagonist (Atkinson et al, 2005) that has high affinity for recombinant human and rat native tissue 5-HT 1A and 5-HT 1B receptors (Scott et al, 2006). [ 3 H]citalopram binding and [ 3 H]5-HT uptake studies have also shown that SB-649915-B has high affinity for human recombinant and rat native SERT (Scott et al, 2006).…”

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

“…Based on preclinical data, one would predict that a compound which incorporated SSRI and 5-HT 1 autoreceptor antagonist properties would have potential to be an effective, rapid onset antidepressant/anxiolytic. oxy] ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one) (Atkinson et al 2005), is a novel 5-HT 1A/B receptor antagonist/5-HT transport inhibitor developed with this hypothesis in mind. SB-649915-B displays high affinity for human (h) 5-HT 1A and 5-HT 1B receptors, (pKi=8.6 and 8.0, respectively) and is a competitive antagonist at both receptors.…”