Abstract

1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)_3A receptor antagonist (K_i = 3.7 nM), h5-HT₇ receptor antagonist (K_i = 19 nM), h5-HT_1B receptor partial agonist (K_i = 33 nM), h5-HT_1A receptor agonist (K_i = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K_i = 1.6 nM) (J Med Chem 54:3206–3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT_1B receptor agonist [EC₅₀ = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT₇ receptor antagonist (K_i = 200 nM and IC₅₀ = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT_1B receptor and rSERT (ED₅₀ = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT₃ receptor antagonist in the Bezold-Jarisch reflex assay (ED₅₀ = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5–10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), 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 3.9 mg/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 for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.