RT Journal Article
SR Electronic
T1 Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 666
OP 675
DO 10.1124/jpet.111.189068
VO 340
IS 3
A1 A. Mørk
A1 A. Pehrson
A1 L. T. Brennum
A1 S. Møller Nielsen
A1 H. Zhong
A1 A. B. Lassen
A1 S. Miller
A1 L. Westrich
A1 N. J. Boyle
A1 C. Sánchez
A1 C. W. Fischer
A1 N. Liebenberg
A1 G. Wegener
A1 C. Bundgaard
A1 S. Hogg
A1 B. Bang-Andersen
A1 T. Bryan Stensbøl
YR 2012
UL http://jpet.aspetjournals.org/content/340/3/666.abstract
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.