Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity

Hatanaka, Ken-ichi; Nomura, Tamako; Hidaka, Kazuyuki; Takeuchi, Haruhiko; Yatsugi, Shin-ichi; Fujii, Mikihisa; Yamaguchi, Tokio

doi:10.1016/s0028-3908(96)00079-2

Cited by 36 publications

(23 citation statements)

References 23 publications

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“…Their order of potency was correlated with their 5-HT re-uptake inhibition activities in the l-5-HTP potentiation study (5). YM992 exhibits 5-HT re-uptake inhibition and 5-HT 2A -receptor antagonistic activity (4,5). This property would contribute to efficacy of YM992 in various tests for evaluating antidepressant activity (5).…”

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confidence: 96%

“…One tricyclic antidepressant (TCA), clomipramine, and four selective 5-HT re-uptake inhibitors (SSRIs), fluvoxamine, fluoxetine, paroxetine and sertraline, are approved by the Food and Drug Administration (FDA) for use in patients with OCD (3). YM992 ((S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine) monohydrochloride is a novel compound with selective 5-HT reuptake inhibition and 5-HT2A receptor antagonistic activity (4). The pharmacological profile of YM992 is different from that of TCAs and SSRIs, and it shows high efficacy in various tests, some of which predict the antidepressant activity of drugs (5).…”

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confidence: 99%

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Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model

Takeuchi¹,

Yatsugi²,

Yamaguchi³

2002

Japanese Journal of Pharmacology

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ABSTRACT-YM992 ((S)-2-[[ (7-fluoroindan-4-yl)oxy]methyl]morpholine) monohydrochloride is a novel antidepressant with selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibition and 5-HT 2A receptor antagonistic activity. The effects of YM992 and two selective 5-HT re-uptake inhibitors (SSRIs) were studied in a marble-burying behavior test as a model of an obsessive-compulsive disorder (OCD) in mice at doses of 5, 10 and 15 mg /kg, i.p. YM992 and fluoxetine significantly inhibited marble-burying behavior at a dose of 15 mg /kg (i.p.) without affecting spontaneous locomotor activities. Citalopram also significantly inhibited the behavior at doses of 5, 10 and 15 mg /kg (i.p.) without affecting spontaneous locomotor activities. These results suggest that YM992, as well as SSRIs, may exhibit anti-OCD activity in addition to an antidepressive effect in clinical use.

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Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model

Takeuchi¹,

Yatsugi²,

Yamaguchi³

2002

Japanese Journal of Pharmacology

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“…It has been demonstrated that SSRIs inhibit this transporter in platelets. 3,4 One study demonstrated an 83% decrease in platelet serotonin concentrations after 2 weeks of therapeutic paroxetine administration. 4 We tested the hypothesis that SSRIs increase the risk for hemorrhagic stroke and potentiate the risk associated with antiplatelet and anticoagulant drugs.…”

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Selective Serotonin Reuptake Inhibitors and Risk of Hemorrhagic Stroke

Kharofa

Sekar

Haverbusch

et al. 2007

Stroke

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Background and Purpose-Selective serotonin reuptake inhibitors (SSRI) are widely prescribed. Several reports have observed an increased bleeding risk associated with SSRI use, which is hypothesized to be secondary to their antiplatelet effect. Methods-We tested the hypothesis that SSRIs increase the risk for or potentiate the risk of hemorrhagic stroke associated with antiplatelets and anticoagulants. Results-In multivariate analysis, we found no increased risk associated with SSRI use for intracerebral hemorrhage (odds ratioϭ1.1, 95% CI: 0.7 to 1.8; Pϭ0.63) or subarachnoid hemorrhage (odds ratioϭ0.6, 95% CI: 0.4 to 1.0; Pϭ0.054).In addition, potentiation of risk with warfarin or antiplatelets was not observed. Conclusions-Further studies with larger populations would be needed to exclude a small increase in intracranial hemorrhage risk with SSRI use.

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“…YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a novel SSRI agent (K i ϭ 21 nM) that enhances 5-HT neurotransmission after long-term (21-day) administration and possesses 5-HT 2A -antagonistic properties (K i ϭ 86 nM; Hatanaka et al, 1996;Dong et al, 1999). In addition to blocking 5-HT reuptake, YM992 may contribute to superior antidepressant and antipanic activities by immediately blocking the 5-HT 2A receptors.…”

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confidence: 99%

Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT_2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons

Szabo¹,

Blier²

2002

J Pharmacol Exp Ther

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YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and a potent 5-HT 2A antagonist. The aim of the present study was to assess, using in vivo extracellular unitary recordings, the effect of acute and sustained administration of YM992 (40 mg kg Ϫ1 day Ϫ1 s.c., using osmotic minipumps) on the spontaneous firing activity of locus coeruleus (LC) norepinephrine (NE) neurons. Acute intravenous injection of YM992 (4 mg kg Ϫ1 ) significantly decreased NE neuron firing activity by 29% and blocked the inhibitory effect of a subsequent injection of the 5-HT 2 agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride]. A 2-day treatment with YM992 decreased the firing rate of NE neurons by 66%, whereas a partial recovery was observed after a 7-day treatment and a complete one after a 21-day treatment. Following the injection of the ␣ 2 -adrenoceptor antagonist idazoxan (1 mg kg -1 i.v.), NE neuron firing was equalized in controls and 2-day YM992-treated rats. This put into evidence an increased degree of activation of ␣ 2 -adrenergic autoreceptors in the treated rats. The suppressant effect of the ␣ 2 -adrenoceptor agonist clonidine was significantly decreased in longterm YM992-treated rats. The recovery of LC firing activity after long-term YM992 administration could thus be explained by a decreased sensitivity of ␣ 2 -adrenergic autoreceptors. Sustained SSRI administration leads to a gradual reduction of the firing activity of NE neurons during long-term administration, whereas YM992 produced opposite effects. The exact basis for the increased synaptic availability of NE by YM992 remains to be elucidated. This NE activity, resulting from 5-HT reuptake inhibition plus 5-HT 2A receptor antagonism, might confer additional benefits in affective and anxiety disorders.The norepinephrine (NE) and the serotonin (5-hydroxytryptamine; 5-HT) systems have both been implicated in anxiety and affective disorders. Although the etiopathology of these two disorders remains enigmatic, greater knowledge exists pertaining to the interactions/alterations of these monoaminergic systems during antidepressant drug treatment. It is well established that locus coeruleus (LC) NE neurons modulate the 5-HT system, and evidence is accumulating for a major influence of 5-HT on the NE system (see Haddjeri et al., 1997;Kaehler et al., 1999). The LC receives dense 5-HT projections coming from dorsal raphe and pericoerulear 5-HT neurons (Aston-Jones et al., 1991;Kaehler et al., 1999), which exert an inhibitory role (Léger and Descarries, 1978;Segal, 1979). This is supported by the observation that lesioning 5-HT neurons with a 5-HT neurotoxin produced a marked elevation of firing rate of NE neurons (Haddjeri et al., 1997). Long-term, but not acute or short-term (2-day) administration of SSRIs decreases the spontaneous firing activity of LC NE neurons in the rat (Béïque et al.,1998;Szabo et al., 2000;Szabo and Blier, 2001a;Grant a...

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Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity

Cited by 36 publications

References 23 publications

Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model

Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model

Selective Serotonin Reuptake Inhibitors and Risk of Hemorrhagic Stroke

Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT_2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons

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Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity

Cited by 36 publications

References 23 publications

Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model

Effect of YM992, a Novel Antidepressant With Selective Serotonin Re-uptake Inhibitory and 5-HT2A Receptor Antagonistic Activity, on a Marble-Burying Behavior Test as an Obsessive-Compulsive Disorder Model

Selective Serotonin Reuptake Inhibitors and Risk of Hemorrhagic Stroke

Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons

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Effects of Serotonin (5-Hydroxytryptamine, 5-HT) Reuptake Inhibition Plus 5-HT_2A Receptor Antagonism on the Firing Activity of Norepinephrine Neurons