Dataset Information

Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

ABSTRACT: Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.

SUBMITTER: Dutta AK

PROVIDER: S-EPMC4245125 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

Dutta Aloke K AK Santra Soumava S Sharma Horrick H Voshavar Chandrashekhar C Xu Liping L Mabrouk Omar O Antonio Tamara T Reith Maarten E A ME

PloS one 20141126 11

Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine trans ...[more]

PMID: 25427177

Similar Datasets

Project description:Importance:In 2006, the US Food and Drug Administration (FDA) issued an advisory warning on the risk of serotonin syndrome with concomitant use of triptans and selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) antidepressants, but the true risk of serotonin syndrome in these patients remains unknown. Objective:To assess the risk of serotonin syndrome with concomitant use of triptans and SSRI or SNRI antidepressants. Design, Setting, and Participants:This study used electronic health record data from the Partners Research Data Registry (RPDR) to identify patients who had received an International Classification of Diseases, Ninth Revision diagnosis compatible with serotonin syndrome who had been coprescribed triptans and SSRI or SNRI antidepressants in the Greater Boston, Massachusetts, area from January 1, 2001, through December 31, 2014 (14 years). Clinical information was extracted to determine whether the case met formal diagnostic criteria and had coprescription within a calendar year. Both conservative and broad case definitions were used to better characterize the spectrum of risk. Data analysis was performed from November 23, 2016, to July 15, 2017. Main Outcomes and Measures:Incidence of serotonin syndrome. Results:The RPDR search revealed 47?968 (±3) unique patients who were prescribed triptans during the 14-year period of the study. A total of 19?017 (±3) patients were coprescribed triptans and antidepressants during the study, with a total of 30?928 person-years of exposure. Serotonin syndrome was suspected in 17 patients. Only 2 patients were classified as having definite serotonin syndrome (incidence rate, 0.6 cases per 10?000 person-years of exposure; 95% CI, 0.0-1.5). Five patients were classified as having possible serotonin syndrome (incidence rate with these 5 cases added to the 2 definite cases, 2.3 cases per 10?000 person-years of exposure; 95% CI, 0.6-3.9). The proportion of patients with triptan prescriptions who were coprescribed an SSRI or SNRI antidepressant was relatively stable during the study, ranging from 21% to 29%. Conclusions and Relevance:The risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low. Coprescription of these drugs is common and did not decrease after the 2006 FDA advisory. Our results cast doubt on the validity of the FDA advisory and suggest that it should be reconsidered.

Project description:BackgroundAnxiety, obsessive-compulsive, and stress-related disorders frequently co-occur, and patients often present symptoms of several domains. Treatment involves the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), but data on comparative efficacy and acceptability are lacking. We aimed to compare the efficacy of SSRIs, SNRIs, and placebo in multiple symptom domains in patients with these diagnoses over the lifespan through a 3-level network meta-analysis.Methods and findingsWe searched for published and unpublished randomized controlled trials that aimed to assess the efficacy of SSRIs or SNRIs in participants (adults and children) with diagnosis of any anxiety, obsessive-compulsive, or stress-related disorder in MEDLINE, PsycINFO, Embase, and Cochrane Library from inception to 23 April 2015, with an update on 11 November 2020. We supplemented electronic database searches with manual searches for published and unpublished randomized controlled trials registered in publicly accessible clinical trial registries and pharmaceutical companies' databases. No restriction was made regarding comorbidities with any other mental disorder, participants' age and sex, blinding of participants and researchers, date of publication, or study language. The primary outcome was the aggregate measure of internalizing symptoms of these disorders. Secondary outcomes included specific symptom domains and treatment discontinuation rate. We estimated standardized mean differences (SMDs) with 3-level network meta-analysis with random slopes by study for medication and assessment instrument. Risk of bias appraisal was performed using the Cochrane Collaboration's risk of bias tool. This study was registered in PROSPERO (CRD42017069090). We analyzed 469 outcome measures from 135 studies (n = 30,245). All medications were more effective than placebo for the aggregate measure of internalizing symptoms (SMD -0.56, 95% CI -0.62 to -0.51, p < 0.001), for all symptom domains, and in patients from all diagnostic categories. We also found significant results when restricting to the most used assessment instrument for each diagnosis; nevertheless, this restriction led to exclusion of 72.71% of outcome measures. Pairwise comparisons revealed only small differences between medications in efficacy and acceptability. Limitations include the moderate heterogeneity found in most outcomes and the moderate risk of bias identified in most of the trials.ConclusionsIn this study, we observed that all SSRIs and SNRIs were effective for multiple symptom domains, and in patients from all included diagnostic categories. We found minimal differences between medications concerning efficacy and acceptability. This three-level network meta-analysis contributes to an ongoing discussion about the true benefit of antidepressants with robust evidence, considering the significantly larger quantity of data and higher statistical power when compared to previous studies. The 3-level approach allowed us to properly assess the efficacy of these medications on internalizing psychopathology, avoiding potential biases related to the exclusion of information due to distinct assessment instruments, and to explore the multilevel structure of transdiagnostic efficacy.

Project description:Genetic loss or pharmacological inhibition of monoamine oxidase A (MAOA) in mice leads to a large increase in whole-brain levels of serotonin (5-HT). Excess 5-HT in mouse neonates prevents the normal barrel-like clustering of thalamic axons in the somatosensory cortex. Projection fields of other neuron populations may develop abnormally. In the present study, we have analyzed the localization of 5-HT immunolabeling in the developing brain of MAOA knock-out mice. We show numerous atypical locations of 5-HT during embryonic and postnatal development. Catecholaminergic cells of the substantia nigra, ventral tegmental area, hypothalamus, and locus ceruleus display transient 5-HT immunoreactivity. Pharmacological treatments inhibiting specific monoamine plasma membrane transporters and genetic crosses with mice lacking the dopamine plasma membrane transporter show that the accumulation of 5-HT in these catecholaminergic cells is attributable to 5-HT uptake via the dopamine or the norepinephrine plasma membrane transporter. In the telencephalon, transient 5-HT immunolabeling is observed in neurons in the CA1 and CA3 fields of the hippocampus, the central amygdala, the indusium griseum, and the deep layers of the anterior cingulate and retrosplenial cortices. In the diencephalon, primary sensory nuclei, as well as the mediodorsal, centrolateral, oval paracentral, submedial, posterior, and lateral posterior thalamic nuclei, are transiently 5-HT immunolabeled. The cortical projections of these thalamic nuclei are also labeled. In the brainstem, neurons in the lateral superior olivary nucleus and the anteroventral cochlear nucleus are transiently 5-HT immunolabeled. None of these structures appear to express the monoamine biosynthetic enzyme L-aromatic amino acid decarboxylase. The administration of monoamine plasma membrane transporter inhibitors indicates that the 5-HT immunolabeling in these structures is attributable to an uptake of 5-HT by the 5-HT plasma membrane transporter. This points to neuron populations that form highly precise projection maps that could be affected by 5-HT during specific developmental stages.

Dataset Information

Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

Publications

Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets