The treatment of depression — searching for new ideas

Stachowicz, Katarzyna; Sowa-Kućma, Magdalena

doi:10.3389/fphar.2022.988648

Cited by 24 publications

(23 citation statements)

References 75 publications

(116 reference statements)

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“…However, while the annual prevalence of a major depressive episode among US adults is 7.1%, more than 30% of the medication-treated patients with major depressive disorder suffer from treatment-resistant depression (1). Thus, there is a significant demand for alternative medications, targeting either hSERT or other targets (2).…”

Section: Introductionmentioning

confidence: 99%

Dynamic extracellular vestibule of human SERT: unveiling druggable potential with novel high-affinity allosteric inhibitors

Salomon

Abramyan

Plenge

et al. 2023

Preprint

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The serotonin transporter (SERT) tightly regulates synaptic serotonin levels and has been the primary target of antidepressants. Binding of inhibitors to the allosteric site of human SERT (hSERT) impedes the dissociation of antidepressants bound at the central site, and may enhance the efficacy of such antidepressants to potentially reduce their dosage and side effects. Here we report the discovery of a series of high-affinity allosteric inhibitors of hSERT in a novel scaffold, with the lead compound, Lu AF88273 (3-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-6-chloro-1H-indole), having 2.1 nM allosteric potency in inhibiting imipramine dissociation. In addition, we find that Lu AF88273 also inhibits the serotonin transport in a non-competitive manner. The binding pose of Lu AF88273 in the allosteric site of hSERT is determined with extensive molecular dynamics simulations and rigorous absolute binding free energy perturbation (FEP) calculations, which show a part of the compound occupies a dynamically formed small cavity. The predicted binding location and pose is validated by a site-directed mutagenesis study, and can explain much of the structure-activity relationship of these inhibitors using the relative binding FEP calculations. Together, our findings provide a promising lead compound and the structural basis for the development of allosteric drugs targeting hSERT. Further, they demonstrate that the divergent allosteric sites of neurotransmitter transporters can be selectively targeted.

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Section: Introductionmentioning

confidence: 99%

Dynamic extracellular vestibule of human SERT: unveiling druggable potential with novel high-affinity allosteric inhibitors

Salomon

Abramyan

Plenge

et al. 2023

Preprint

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“…Pharmacological therapy for MDD is based on medications discovered in the 1960s and the early 1970s, SSRIs, and serotonin-NE reuptake inhibitors (SNRIs). 30 However, these medications have limitations, such as a long administration time to obtain a therapeutic effect, and their use is associated with many side effects, including weight gain, sexual dysfunction, dizziness, headache, anxiety, psychosis, and cognitive dysfunction. 31,32 DA is a monoaminergic neurotransmitter responsible for regulating several functions including mood, motivation, pleasure, and reward.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…MDD is a heterogeneous disorder, both in terms of symptoms ranging from anhedonia to cognitive impairment and pathophysiology, with a combination of genetic, epigenetic, and environmental factors. , Therefore, it is unlikely that depressive symptoms can be completely controlled by a drug with a single mechanism of action. Pharmacological therapy for MDD is based on medications discovered in the 1960s and the early 1970s, SSRIs, and serotonin-NE reuptake inhibitors (SNRIs) . However, these medications have limitations, such as a long administration time to obtain a therapeutic effect, and their use is associated with many side effects, including weight gain, sexual dysfunction, dizziness, headache, anxiety, psychosis, and cognitive dysfunction. , …”

Section: Resultsmentioning

confidence: 99%

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide

Besckow,

Ledebuhr,

Pires

et al. 2024

ACS Chem. Neurosci.

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The compound N- (3-(phenylselanyl)prop-2-yn-1yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D 1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D 2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α 1 -adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α 2 -adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

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“…This is mostly due to cardiometabolic disease related to chronic treatments and physical inactivity ( 6 ). The high levels of treatment resistance, undesirable side effects, and the high economic and social cost to society have prompted a diversification of the search for effective treatment options ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

The effects of physical activity on glutamate neurotransmission in neuropsychiatric disorders

Baskerville

McGrath²,

Castell³

2023

Front. Sports Act. Living

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Physical activity (PA) is an effective way of increasing cognitive and emotional health and counteracting many psychiatric conditions. Numerous neurobiological models for depression have emerged in the past 30 years but many struggle to incorporate the effects of exercise. The hippocampus and pre-frontal cortex (PFC) containing predominantly glutamate neurotransmission, are the centres of changes seen in depression. There is therefore increasing interest in glutamatergic systems which offers new paradigms of understanding mechanisms connecting physical activity, stress, inflammation and depression, not explained by the serotonin theories of depression. Similar hippocampal glutamate dysfunction is observed in many other neuropsychiatric conditions. Excitatory glutamate neurones have high functionality, but also high ATP requirements and are therefore vulnerable to glucocorticoid or pro-inflammatory stress that causes mitochondrial dysfunction, with synaptic loss, culminating in depressed mood and cognition. Exercise improves mitochondrial function, angiogenesis and synaptogenesis. Within the glutamate hypothesis of depression, the mechanisms of stress and inflammation have been extensively researched, but PA as a mitigator is less understood. This review examines the glutamatergic mechanisms underlying depression and the evidence of physical activity interventions within this framework. A dynamic glutamate-based homeostatic model is suggested whereby stress, neuroinflammation and PA form counterbalancing influences on hippocampal cell functionality, which manifests as depression and other neuropsychiatric conditions when homeostasis is disrupted.

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The treatment of depression — searching for new ideas

Cited by 24 publications

References 75 publications

Dynamic extracellular vestibule of human SERT: unveiling druggable potential with novel high-affinity allosteric inhibitors

Dynamic extracellular vestibule of human SERT: unveiling druggable potential with novel high-affinity allosteric inhibitors

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide

The effects of physical activity on glutamate neurotransmission in neuropsychiatric disorders

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