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-HT(7) 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 [EC(50) = 460 nM, intrinsic 
activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu 
AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 
2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) 
= 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 
5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 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-HT(3) 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.