S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α<sub>2</sub>-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

Millan, Mark J.; Cour, Clotilde Mannoury la; Chanrion, Benjamin; Dupuis, Delphine S.; Cara, Benjamin Di; Audinot, Valérie; Cussac, Didier; Newman‐Tancredi, Adrian; Kamal, Maud; Boutin, Jean A.; Jockers, Ralf; Marin, Philippe; Bockaert, Joël; Müller, Olivier; Dekeyne, Anne; Lavielle, Gilbert

doi:10.1124/jpet.111.187468

Cited by 16 publications

(28 citation statements)

References 77 publications

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“…The LANCE cAMP kit (PerkinElmer, Zaventem, Belgium) was used to determine cAMP concentrations according to the manufacturer's instruction [26], [27]. Briefly, the cells were grown to 80% confluence, harvested with versene, and washed once with HBSS.…”

Section: Methodsmentioning

confidence: 99%

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

Chen¹,

Jin

Zhang³

et al. 2013

PLoS ONE

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It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder.

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Section: Methodsmentioning

confidence: 99%

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

Chen¹,

Jin

Zhang³

et al. 2013

PLoS ONE

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“…We first checked the specificity of the inhibitor S29434 for possible off-target activities (from the QR2 perspective). First, we assessed its activity in a series of standard assays designed to evaluate its behavior against a selection of receptors and enzymes [see, for example, Millan et al (2012)]. All tests were performed in duplicate, independently, at two concentrations: 100 nM and 10 mM.…”

Section: Resultsmentioning

confidence: 99%

S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

et al. 2018

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Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl-and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC 50 5 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases. E.C.H. and P.P.M. acknowledge the support of the funding programs "Investissements d'avenir" ANR-10-IAIHU-06 and "Investissements d'avenir" ANR-11-INBS-0011-NeurATRIS: Translational Research Infrastructure for Biotherapies in Neurosciences. This work benefited from equipment and services from the CELIS core facility (Institut du Cerveau et de la Moelle Epinière, Paris). Dr. D.A.K. acknowledges support from the Canada Foundation for Innovation and the Natural Sciences and Engineering Research Council of Canada. Dr. E.J. received financial support from Herbal and Antioxidant Derivatives srl, Biano (RC), Italy, and from FFARB 2017 (Basic Research Activities Fund).

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“…Inverse agonism is a well-known mechanism of ligand action observed for constitutively active receptors [ 50 ] and has great therapeutic significance as a variety of clinically used drugs like β-blockers [ 51 ] and anti-allergic drugs targeting the histamine H1 receptor [ 52 ] act as inverse agonists [ 53 , 54 ]. The potential antidepressant S32212 showed inverse agonistic action at the serotonin receptor 2C in reducing basal IP 3 production mediated via G q/11 activation [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5

et al. 2015

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Objective Application of 3-iodothyronamine (3-T1AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T1AM. However, 3-T1AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T1AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct Gs-, Gi/o-, G12/13-, Gq/11- and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T1AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the Gq/11 pathway but show differences in the basal activity in Gs and MAP kinase signaling. In contrast to mTaar5, 3-T1AM application at hTAAR5 resulted in significant reduction in basal IP3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T1AM-mediated effects may differ between rodents and humans.

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S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α₂-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

Cited by 16 publications

References 77 publications

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5

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S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

Cited by 16 publications

References 77 publications

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

S29434, a Quinone Reductase 2 Inhibitor: Main Biochemical and Cellular Characterization

Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5

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S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α₂-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization