Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (K-i < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long formof human D-2 (hD(2L))-, h alpha(1B)-, and h alpha(2C)-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD(2) receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and h alpha(1B/2C)-adrenoceptors. Brexpiprazole also had affinity (K-i < 5 nM) for hD(3)-, h5-HT2B-, h5-HT7-, h alpha(1A)-, and h alpha(1D)-adrenergic receptors, moderate affinity for hH(1) (K-i = 19 nM), and low affinity for hM(1) receptors (K-i > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D-2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D-2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D-2 partial agonist activity. In particular, based on a lower intrinsic activity at D-2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D-2 receptor agonistand antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.