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 jpet.111.189068
DO 10.1124/jpet.111.189068
A1 Arne Mork
A1 Alan Pehrson
A1 Lise Tottrup Brennum
A1 Soren Moller Nielsen
A1 Huailing Zhong
A1 Anders B. Lassen
A1 Silke Miller
A1 Ligia Westrich
A1 Noel J. Boyle
A1 Connie Sanchez
A1 Christina Weide Fischer
A1 Nico Liebenberg
A1 Gregers Wegener
A1 Christoffer Bundgaard
A1 Sandra Hogg
A1 Benny Bang-Andersen
A1 Tine Bryan Stensbol
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/12/09/jpet.111.189068.abstract
AB Lu AA21004 (1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a human serotonin (h5-HT)3A receptor antagonist (Ki=3.7nM), h5-HT7 receptor antagonist (Ki=19nM), h5-HT1B receptor partial agonist (Ki=33nM), h5-HT1A receptor agonist (Ki=15nM) and a h5-HT transporter (hSERT) inhibitor (Ki=1.6nM) (Bang-Andersen et al., 2011). Here we confirm that Lu AA21004 is a partial h5-HT1B receptor agonist (EC50=460nM, IA=22%) using a whole cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r)5-HT7 receptor antagonist (Ki=200nM and IC50=2080nM). In vivo, Lu AA21004 occupies the r5-HT1B receptor and rSERT (ED50=3.2mg/kg and 0.4mg/kg, respectively) after subcutaneous (sc) administration and is a 5-HT3 receptor antagonist in the Bezold-Jarisch reflex assay (ED50=0.11mg/kg sc). In rat microdialysis experiments, Lu AA21004 (2.5-10.0mg/kg sc) increased extracellular 5-HT, dopamine and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004, 5mg/kg/day for 3 days (minipumps sc), 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 3.9mg/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 where targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from current antidepressants.