Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder.

Lu AA21004 (1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a human serotonin (h5-HT)3A receptor antagonist (Ki=3.7nM), h5-HT7 receptor antagonist (Ki=19nM), h5-HT1B receptor partial agonist (Ki=33nM), h5-HT1A receptor agonist (Ki=15nM) and a h5-HT transporter (hSERT) inhibitor (Ki=1.6nM) (Bang-Andersen et al., 2011). Here we confirm that Lu AA21004 is a partial h5-HT1B receptor agonist (EC50=460nM, IA=22%) using a whole cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r)5-HT7 receptor antagonist (Ki=200nM and IC50=2080nM). In vivo, Lu AA21004 occupies the r5-HT1B receptor and rSERT (ED50=3.2mg/kg and 0.4mg/kg, respectively) after subcutaneous (sc) administration and is a 5-HT3 receptor antagonist in the Bezold-Jarisch reflex assay (ED50=0.11mg/kg sc). In rat microdialysis experiments, Lu AA21004 (2.5-10.0mg/kg sc) increased extracellular 5-HT, dopamine and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004, 5mg/kg/day for 3 days (minipumps sc), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT3 receptor antagonist, ondansetron potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0 and 3.9mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses where targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from current antidepressants.