S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models

Dekeyne, Anne; Cour, Clotilde Mannoury la; Gobert, Alain P.; Brocco, Mauricette; Lejeune, Françoise; Serres, Florence; Sharp, Trevor; Daszuta, Annie; Soumier, Amélie; Papp, Mariusz; Rivet, Jean‐Michel; Flik, Gunnar; Cremers, Thomas; Müller, Olivier; Lavielle, Gilbert; Millan, Mark J.

doi:10.1007/s00213-008-1177-9

Cited by 110 publications

(98 citation statements)

References 115 publications

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“…These results further suggest that this regional stimulatory effect of agomelatine on cell proliferation is not mediated by melatonin receptors, but rather by the blockade of 5-HT 2C receptors. Indeed, two different 5-HT 2C receptor antagonists, SB243,213 and S32006 (Wood et al, 2001;Dekeyne et al, 2008), mimicked agomelatine's effect on cell proliferation in the VH only. In line with these observations, it has also been demonstrated that 5-HT 2C receptor-binding sites are more densely expressed in the VH compared with DH (Holmes et al, 1995).…”

Section: Adult Neurogenesis and Antidepressantmentioning

confidence: 98%

“…All procedures were conducted in accordance with the French Agriculture and Forestry Ministry (decree 87848, license 01498). SB242,084, a selective 5-HT 2C receptor neutral antagonist (Kennett et al, 1997), SB243,213, a selective 5-HT 2C receptor inverse agonist (Wood et al, 2001), and S32006, a novel 5-HT 2C receptor inverse agonist (Dekeyne et al, 2008), were injected once a day, at 10 mg/kg i.p. dissolved in sterile water or 1% hydroxyethylcellulose (HEC).…”

Section: Animals and Drug Treatmentsmentioning

confidence: 99%

“…dissolved in sterile water or 1% hydroxyethylcellulose (HEC). Doses of 5-HT 2C antagonists were selected on the basis of the well-characterized actions of these drugs in functional studies performed both in our laboratory and elsewhere (Di Matteo et al, 1999;Kennett et al, 1997;Wood et al, 2001;Dekeyne et al, 2008). Agomelatine was injected as a suspension in 1% HEC at 40 mg/kg i.p.…”

Section: Animals and Drug Treatmentsmentioning

confidence: 99%

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Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

Soumier¹,

Banasr²,

Lortet³

et al. 2009

Neuropsychopharmacol

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145

138

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Agomelatine is a novel antidepressant acting as a melatonergic receptor agonist and serotonergic (5-HT 2C ) receptor antagonist. In adult rats, chronic agomelatine treatment enhanced cell proliferation and neurogenesis in the ventral hippocampus (VH), a region pertinent to mood disorders. This study compared the effects of agomelatine on cell proliferation, maturation, and survival and investigated the cellular mechanisms underlying these effects. Agomelatine increased the ratio of mature vs immature neurons and enhanced neurite outgrowth of granular cells, suggesting an acceleration of maturation. The influence of agomelatine on maturation and survival was accompanied by a selective increase in the levels of BDNF (brain-derived neurotrophic factor) vs those of VEGF (vascular endothelial factor) and IGF-1 (insulin-like growth factor 1), which were not affected. Agomelatine also activated several cellular signals (extracellular signal-regulated kinase1/2, protein kinase B, and glycogen synthase kinase 3b) known to be modulated by antidepressants and implicated in the control of proliferation/survival. Furthermore, as agomelatine possesses both melatonergic agonist and serotonergic (5-HT 2C ) antagonist properties, we determined whether melatonin and 5-HT 2C receptor antagonists similarly influence cell proliferation and survival. Only the 5-HT 2C receptor antagonists, SB243,213 or S32006, but not melatonin, mimicked the effects of agomelatine on cell proliferation in VH. The promoting effect of agomelatine on survival was not reproduced by the 5-HT 2C receptor antagonists or melatonin alone. However, it was blocked by a melatonin antagonist, S22153. These results show that agomelatine treatment facilitates all stages of neurogenesis and suggest that a joint effect of melatonin agonism and 5HT 2C antagonism may be involved in promotion by agomelatine of survival in the hippocampus.

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Section: Adult Neurogenesis and Antidepressantmentioning

confidence: 98%

Section: Animals and Drug Treatmentsmentioning

confidence: 99%

Section: Animals and Drug Treatmentsmentioning

confidence: 99%

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Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

Soumier¹,

Banasr²,

Lortet³

et al. 2009

Neuropsychopharmacol

Self Cite

145

138

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show abstract

“…[85][86][87] In addition, blockade of ventrotegmental-and locus ceruleus-localized 5-HT 2C sites disinhibits dopaminergic and adrenergic pathways, respectively, and 5-HT 2C antagonists elicit robust antidepressant and anxiolytic actions in a broad range of paradigms. 40,85,86,88 -90 Blockade of 5-HT 2C sites may, further, enhance sexual function and improve restorative slow wave sleep, 42,85,91 and antagonism of hypothalamic 5-HT 2C receptors facilitatory to the hypothalamo-pituitary-adrenocortical (HPA) axis abrogates its overstimulation by stress.…”

Section: Bimodal Antidepressants Acting As 5-ht 2c or 5-ht 2a Receptomentioning

confidence: 99%

“…68,116 5-HT 1B receptors have also been forwarded as mediators of antidepressant actions of SSRIs, together with 5-HT 2A and (controversially) 5-HT 2C and 5-HT 6 sites; 5-HT 4 receptors were also recently added to the inventory of potential serotonergic mechanisms for improving mood. 3,58,86,[117][118][119] No single receptor can account for the global therapeutic influence of antidepressants that increase monoamine levels. For example, cellular substrates controlling neurogenesis in the hippocampus differ from those that counter anhedonia.…”

Section: Recruiting Subsets Of Postsynaptic Sites Mediating Beneficiamentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

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123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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Antidepressants

Glennon¹,

Iversen²

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain‐derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, corticotrophin releasing factor receptors, or agonists/antagonists for galanin receptors.

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S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models

Abstract: S32006 is a potent 5-HT(2C) receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models.

Cited by 110 publications

References 115 publications

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Antidepressants

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