PT  - JOURNAL ARTICLE
AU  - A. Mørk
AU  - A. Pehrson
AU  - L. T. Brennum
AU  - S. Møller Nielsen
AU  - H. Zhong
AU  - A. B. Lassen
AU  - S. Miller
AU  - L. Westrich
AU  - N. J. Boyle
AU  - C. Sánchez
AU  - C. W. Fischer
AU  - N. Liebenberg
AU  - G. Wegener
AU  - C. Bundgaard
AU  - S. Hogg
AU  - B. Bang-Andersen
AU  - T. Bryan Stensbøl
TI  - Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
AID  - 10.1124/jpet.111.189068
DP  - 2012 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 666--675
VI  - 340
IP  - 3
4099  - http://jpet.aspetjournals.org/content/340/3/666.short
4100  - http://jpet.aspetjournals.org/content/340/3/666.full
SO  - J Pharmacol Exp Ther2012 Mar 01; 340
AB  - 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 54:3206–3221, 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 (2.5–10.0 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.