Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
| Autor: | Christoffer Bundgaard, Ligia Westrich, Arne Mørk, Benny Bang-Andersen, T. Bryan Stensbøl, Christina W. Fischer, Samuel I. Miller, Sandra Hogg, Nico Liebenberg, Gregers Wegener, Alan L. Pehrson, Connie Sanchez, H. Zhong, Lise T. Brennum, A.B. Lassen, N. J. Boyle, S. Møller Nielsen |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Agonist medicine.medical_specialty Microdialysis Intrinsic activity medicine.drug_class Citalopram Sulfides Pharmacology Partial agonist Piperazines Rats Sprague-Dawley Internal medicine Reflex medicine Animals Humans Serotonin receptor antagonist Biogenic Monoamines Receptor Serotonin Plasma Membrane Transport Proteins Depressive Disorder Major Chemistry Receptor antagonist Ondansetron Rats Endocrinology Anti-Anxiety Agents Receptors Serotonin Receptor Serotonin 5-HT1B Molecular Medicine Vortioxetine Serotonin Vocalization Animal |
| Zdroj: | Mork, A, Pehrson, A, Tottrup Brennum, L, Moller Nielsen, S, Zhong, H, Lassen, A B, Miller, S, Westrich, L, Boyle, N J, Sanchez, C, Fischer, C, Liebenberg, N, Wegener, G, Bundgaard, C, Hogg, S, Bang-Andersen, B & Bryan Stensbol, 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 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.111.189068 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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