@article {M{\o}rk666, author = {A. M{\o}rk and A. Pehrson and L. T. Brennum and S. M{\o}ller Nielsen and H. Zhong and A. B. Lassen and S. Miller and L. Westrich and N. J. Boyle and C. S{\'a}nchez and C. W. Fischer and N. Liebenberg and G. Wegener and C. Bundgaard and S. Hogg and B. Bang-Andersen and T. Bryan Stensb{\o}l}, title = {Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder}, volume = {340}, number = {3}, pages = {666--675}, year = {2012}, doi = {10.1124/jpet.111.189068}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)3A receptor antagonist (Ki = 3.7 nM), h5-HT7 receptor antagonist (Ki = 19 nM), h5-HT1B receptor partial agonist (Ki = 33 nM), h5-HT1A receptor agonist (Ki = 15 nM), and a human 5-HT transporter (SERT) inhibitor (Ki = 1.6 nM) (J Med Chem 54:3206{\textendash}3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT1B 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 (Ki = 200 nM and IC50 = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT1B 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{\textendash}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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/340/3/666}, eprint = {https://jpet.aspetjournals.org/content/340/3/666.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }