Characterization of the Potent 5-HT1A /B Receptor Antagonist and Serotonin Reuptake Inhibitor SB-649915: Preclinical Evidence for Hastened Onset of Antidepressant/Anxiolytic Efficacy

Abstract

An increase in brain serotonin (5-HT) levels is thought to be a key mechanism of action responsible for generating antidepressant efficacy. It has been proven that selective serotonin reuptake inhibitors are effective antidepressants, but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT_1A, and possibly 5-HT_1B, autoreceptors to desensitize. Therefore, an agent incorporating 5-HT reuptake inhibition coupled with 5-HT_1A and/or 5-HT_1B autoreceptor antagonism may provide a fast-acting clinical agent. The current studies review the profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound with high affinity for human (h) 5-HT_1A and 5-HT_1B receptors (pK_i values of 8.6 and 8.0, respectively) as well as the (h) 5-HT transporter (SERT) (pK_i value of 9.3). SB-649915 behaved as an antagonist at both 5-HT_1A and 5-HT_1B receptors in vitro and in vivo, reversing 5-HT, (+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and SKF99101-induced functional/behavioral responses. Furthermore, it inhibited [³H]5-HT reuptake in rat cortical synaptosomes, in vitro and ex vivo. In electrophysiological studies SB-649915 had no effect on rat dorsal raphe neuronal cell firing per se, but reversed 8-OH-DPAT–induced inhibition of firing both in vitro and in vivo. In addition, in a microdialysis study, it produced an acute increase in extracellular 5-HT in forebrain structures of the rat. Finally, SB-649915 demonstrated acute anxiolytic activity in both rodent and non-human primate and reduced the latency to onset of anxiolytic behavior, compared to paroxetine, in the rat social interaction paradigm. In summary, SB-649915 is a novel, potent 5-HT_1A/1B autoreceptor antagonist, and 5-HT reuptake inhibitor. This particular pharmacological profile provides a novel mechanism that could offer fast-acting antidepressant activity.