Pharmacological effects of Lu AA21004: A novel multimodal compound for the treatment of major depressive disorder

Arne Mørk, A. Pehrson, L. T. Brennum, S. Møller Nielsen, H. Zhong, A. B. Lassen, S. Miller, L. Westrich, N. J. Boyle, C. Sánchez, C. W. Fischer, N. Liebenberg, G. Wegener, C. Bundgaard, S. Hogg, B. Bang-Andersen, T. Bryan Stensbøl

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)666-675
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume340
Issue number3
DOIs
StatePublished - 1 Mar 2012

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Combined Modality Therapy
Major Depressive Disorder
Pharmacology
Serotonin Receptors
Serotonin
Antidepressive Agents
Anti-Anxiety Agents
Hippocampus
vortioxetine
Ondansetron
Citalopram
Microdialysis
Interpersonal Relations
Prefrontal Cortex
Fear
Neurotransmitter Agents
Reflex
Dopamine
Norepinephrine

Cite this

Mørk, Arne ; Pehrson, A. ; Brennum, L. T. ; Møller Nielsen, S. ; Zhong, H. ; Lassen, A. B. ; Miller, S. ; Westrich, L. ; Boyle, N. J. ; Sánchez, C. ; Fischer, C. W. ; Liebenberg, N. ; Wegener, G. ; Bundgaard, C. ; Hogg, S. ; Bang-Andersen, B. ; Bryan Stensbøl, T. / Pharmacological effects of Lu AA21004 : A novel multimodal compound for the treatment of major depressive disorder. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 340, No. 3. pp. 666-675.
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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.",
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Mørk, A, Pehrson, A, Brennum, LT, Møller Nielsen, S, Zhong, H, Lassen, AB, Miller, S, Westrich, L, Boyle, NJ, Sánchez, C, Fischer, CW, Liebenberg, N, Wegener, G, Bundgaard, C, Hogg, S, Bang-Andersen, B & Bryan Stensbøl, T 2012, 'Pharmacological effects of Lu AA21004: A novel multimodal compound for the treatment of major depressive disorder', Journal of Pharmacology and Experimental Therapeutics, vol. 340, no. 3, pp. 666-675. https://doi.org/10.1124/jpet.111.189068

Pharmacological effects of Lu AA21004 : A novel multimodal compound for the treatment of major depressive disorder. / Mørk, Arne; Pehrson, A.; Brennum, L. T.; Møller Nielsen, S.; Zhong, H.; Lassen, A. B.; Miller, S.; Westrich, L.; Boyle, N. J.; Sánchez, C.; Fischer, C. W.; Liebenberg, N.; Wegener, G.; Bundgaard, C.; Hogg, S.; Bang-Andersen, B.; Bryan Stensbøl, T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 340, No. 3, 01.03.2012, p. 666-675.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacological effects of Lu AA21004

T2 - A novel multimodal compound for the treatment of major depressive disorder

AU - Mørk, Arne

AU - Pehrson, A.

AU - Brennum, L. T.

AU - Møller Nielsen, S.

AU - Zhong, H.

AU - Lassen, A. B.

AU - Miller, S.

AU - Westrich, L.

AU - Boyle, N. J.

AU - Sánchez, C.

AU - Fischer, C. W.

AU - Liebenberg, N.

AU - Wegener, G.

AU - Bundgaard, C.

AU - Hogg, S.

AU - Bang-Andersen, B.

AU - Bryan Stensbøl, T.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - 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.

AB - 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.

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