Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

Hughes, Zoë A.; Starr, Kathryn R.; Scott, Claire M.; Newson, Michael J F; Sharp, Trevor; Watson, Jeannette M.; Hagan, Jim J.; Dawson, Lee A.

doi:10.1007/s00213-006-0691-x

Cited by 28 publications

(23 citation statements)

References 56 publications

(67 reference statements)

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“…in the forebrains of guinea pigs and rats following acute administration (Hughes et al, 2007). Here, we evaluate the effects of SB-649915-B following acute and chronic administration in preclinical tests of anxiety-like behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, SSRIs and 5-HT 1A/B receptor antagonists have been shown to modulate several other neurotransmitter systems including glutamate (Marcoli et al, 1999;Schechter et al, 2002), acetylcholine (Consolo et al, 1996;Nakai et al, 1998;Koyama et al, 1999), dopamine (Boulenguez et al, 1996;Nomikos et al, 1996;Iyer and Bradberry, 1996), and noradrenaline (Hajos-Korcsok et al, 1999) which may contribute to or mediate the SB-649915-B-induced effect. However, the studies to address the effects on systems other than the 5-HT and monoaminergic (Hughes et al, 2007), have, as yet, not been performed.…”

Section: Discussionmentioning

confidence: 99%

“…SB-649915-B also has a good selectivity profile against other 5-HT, dopamine, and adrenergic (a 1B and b 2 ) receptors (Atkinson et al, 2005;Scott et al, 2006). In vivo SB-649915-B shows antagonism at 5-HT 1A and 5-HT 1B receptors as determined by the dose-dependent inhibition of 8-OH-DPAT-induced hyperlocomotion and SKF-99101-H-induced increase in seizure threshold (Hughes et al, 2007) respectively. Ex vivo [ 3 H]5-HT uptake studies have also determined the functional activity of SB-649915-B at the serotonin transporter following oral dosing in rodents (Hughes et al, 2007).…”

Section: Introductionmentioning

confidence: 94%

“…In vivo SB-649915-B shows antagonism at 5-HT 1A and 5-HT 1B receptors as determined by the dose-dependent inhibition of 8-OH-DPAT-induced hyperlocomotion and SKF-99101-H-induced increase in seizure threshold (Hughes et al, 2007) respectively. Ex vivo [ 3 H]5-HT uptake studies have also determined the functional activity of SB-649915-B at the serotonin transporter following oral dosing in rodents (Hughes et al, 2007). The studies described herein determine the effects of SB-649915-B after acute administration in the rat pup ultrasonic vocalization and marmoset human threat tests, and evaluate the temporal nature of these effects in the high light SI model.…”

Section: Introductionmentioning

confidence: 98%

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SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Neuropsychopharmacol

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Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (7) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT 1A/B receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED 50 of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [ 3 H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (po0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Neuropsychopharmacol

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show abstract

“…5). [71][72][73] Its putative antidepressant profile remains uncertain and, like the ligands already discussed, SB-649915-B blocks postsynaptic 5-HT 1A and 5-HT 1B sites-which, rather awkwardly, may participate in the mood-improving actions of SSRIs. 3 Possibly, other components of depressive states such as cognitive deficits and sexual dysfunction will be improved by this intriguing drug.…”

Section: Figmentioning

confidence: 99%

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

Millan¹

2009

Neurotherapeutics

177

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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DSP‐1053, a novel serotonin reuptake inhibitor with 5‐HT_1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats

Kato

Matsumoto

Yamamoto

et al. 2015

Pharmacology Res & Perspec

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Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the Ki values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg−1, dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg−1) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg−1) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.

show abstract

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

Cited by 28 publications

References 56 publications

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

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

DSP‐1053, a novel serotonin reuptake inhibitor with 5‐HT_1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats

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Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

Cited by 28 publications

References 56 publications

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

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

DSP‐1053, a novel serotonin reuptake inhibitor with 5‐HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats

Contact Info

Product

Resources

About

DSP‐1053, a novel serotonin reuptake inhibitor with 5‐HT_1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats