Serotonergic System and Its Role in Epilepsy and Neuropathic Pain Treatment: A Review Based on Receptor Ligands

Pańczyk, Katarzyna; Golda, Sylwia; Waszkielewicz, Anna M.; Żelaszczyk, Dorota; Gunia‐Krzyżak, Agnieszka; Marona, Henryk

doi:10.2174/1381612821666141121114917

Cited by 33 publications

(33 citation statements)

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“…The adrenergic and serotonin receptors were selected as the secondary targets of concern because the adrenergic alpha-2 receptors have effects on heart rate and blood pressure [40] and the serotonin receptors are associated with psychological functions such as aggression, anxiety, and depression [41]. In addition, serotonin neurotransmission has a complex role in seizure pathogenesis [42].…”

Section: Plos Onementioning

confidence: 99%

Evaluating kratom alkaloids using PHASE

et al. 2020

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Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.

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Section: Plos Onementioning

confidence: 99%

Evaluating kratom alkaloids using PHASE

et al. 2020

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“…We also refer to the review paper by Panczyk et al (2015) who listed the evidence for the involvement of 5-HT 1A , 5-HT 2C , 5-HT 3 , 5-HT 4 , and 5-HT 7 Rs as well as the 5-HT transporter (SERT) in epilepsy (Panczyk et al, 2015). …”

Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencementioning

confidence: 99%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

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A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

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“…Compounds were subject to receptor binding preliminary screening (Table ) successively, in the order of their synthesis. Basing on literature review and our former research, evaluations covered receptors 5‐HT 1A , 5‐HT 2A , 5‐HT 6 , 5‐HT 7 , D 2 and α 1 . Compounds 1 , 2 , 5 , 6 , 9 and 11 showed promising receptor profiles, where K i are in nanomolar range.…”

Section: Resultsmentioning

confidence: 99%

“…However, recently in case of depression other mediators are mentioned in this context, e. g. glutamate, GABA, BDNF, allopregnanolone, neuropeptides, thyroid hormone, corticosteroids, sexual hormones and cannabinoids . The involvement of many of these pathways has been also proved for pathophysiology of epilepsy . These findings are supported by the observed diverse therapeutic or adverse effects of drugs targeting monoamine pathways within central nervous system depending on the dose.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N‐(phenoxyalkyl)‐, N‐{2‐[2‐(phenoxy)ethoxy]ethyl}‐ or N‐(phenoxyacetyl)piperazine Derivatives and Their Activity Within the Central Nervous System

et al. 2019

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Depression, anxiety and epilepsy share some etiology factors, causing frequently observed multimodal activity of centrally active compounds. This might raise the risk of central adverse effects of potential drugs, but on the other hand ‐ in a light of common comorbidity of these diseases ‐ also make an opportunity for avoiding polypragmasy. The presented study combines rational drug design methods, chemical synthesis, receptor studies and in vivo pharmacological screening (mice, i. p.) in order to obtain new centrally active piperazine derivatives in a context of their potential multimodality, investigate the mechanism of their activity and establish relationship between their structure, molecular mechanism and in vivo central activity(‐ies). The most promising pharmacological profile showed 1‐(2‐(2,5‐dimethylphenoxy)ethyl)‐4‐phenylpiperazine dihydrochloride (1), which was active in the four‐plate test (anxiolytic‐like activity) at 1.25 mg/kg b.w. and possessed high affinities towards several tested molecular targets (5‐HT1A Ki=35 nM ‐ weak antagonist, 5‐HT2A Ki=121 nM, 5‐HT7 Ki=130 nM ‐ weak antagonist, α1 Ki=82 nM, μ Ki=240 nM).

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Serotonergic System and Its Role in Epilepsy and Neuropathic Pain Treatment: A Review Based on Receptor Ligands

Cited by 33 publications

References 0 publications

Evaluating kratom alkaloids using PHASE

Evaluating kratom alkaloids using PHASE

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Synthesis of N‐(phenoxyalkyl)‐, N‐{2‐[2‐(phenoxy)ethoxy]ethyl}‐ or N‐(phenoxyacetyl)piperazine Derivatives and Their Activity Within the Central Nervous System

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