title: Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder.
abstract: 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.
authors.affiliation: Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark. arm@lundbeck.com
authors.forename: A
authors.initials: A
authors.lastname: Mørk
authors.forename: A
authors.initials: A
authors.lastname: Pehrson
authors.forename: L T
authors.initials: LT
authors.lastname: Brennum
authors.forename: S Møller
authors.initials: SM
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.forename: A B
authors.initials: AB
authors.lastname: Lassen
authors.forename: S
authors.initials: S
authors.lastname: Miller
authors.forename: L
authors.initials: L
authors.lastname: Westrich
authors.forename: N J
authors.initials: NJ
authors.lastname: Boyle
authors.forename: C
authors.initials: C
authors.lastname: Sánchez
authors.forename: C W
authors.initials: CW
authors.lastname: Fischer
authors.forename: N
authors.initials: N
authors.lastname: Liebenberg
authors.forename: G
authors.initials: G
authors.lastname: Wegener
authors.forename: C
authors.initials: C
authors.lastname: Bundgaard
authors.forename: S
authors.initials: S
authors.lastname: Hogg
authors.forename: B
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: T Bryan
authors.initials: TB
authors.lastname: Stensbøl
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D015306:Biogenic Monoamines / Q000032:analysis; D015283:Citalopram / Q000494:pharmacology; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D008297:Male; D017294:Ondansetron / Q000494:pharmacology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013440:Sulfides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014828:Vocalization, Animal / Q000187:drug effects; D000078784:Vortioxetine
chemical_list: D014151:Anti-Anxiety Agents; D015306:Biogenic Monoamines; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides; C104425:serotonin 7 receptor; D015283:Citalopram; D000078784:Vortioxetine; D017294:Ondansetron