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Neurotransmitter-Related Molecular Modeling Studies

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Molecular Structure".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 67199

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Prof. Dr. Alicja Nowaczyk

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Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland
Interests: organic and medicinal chemistry; computational chemistry and molecular modeling of GAT, MAT, VGIC; predictive modelling of detailed mechanisms of action and pharmacological effec-tiveness of biologically active compounds and chemical reaction pathways; neuropharmacology; cardiovascular; safety pharmacology
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Prof. Dr. Grzegorz Grześk

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Department of Cardiology and Clinical Pharmacology, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 75 Ujejskiego St., 85-168 Bydgoszcz, Poland
Interests: clinical and experimental pharmacology; cardiovascular pharmacology; internal medicine; en-dothelial function; vascular smooth muscle function; direct oral anticoagulants; therapeutic drug monitoring; antiplatelets agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The year 2021 is the 100th anniversary of the confirmation of the neurotransmission phenomenon by Otto Lewi. For this reason, we invite you to participate in the celebration of this event by participating in a Special Issue of Molecules devoted to neurotransmission-related phenomena.

Neurotransmitters are chemicals that enable communication, i.e., the flow of nerve impulses between nerve cells, or between nerve cells and muscles and glands. Recently, one can distinguish excitatory and inhibitory mediators, which are both endo–exogenous compounds that control the function of the whole organism. From a chemical point of view, neurotransmitters belong to many different structural groups, such as amino acids (such as glycine), peptides (such as substance P, somatostatin), monoamines (such as noradrenaline or dopamine), purine derivatives (such as adenosine), gases (such as nitrogen, NO, carbon monoxide CO) or acetylcholine. From a medical point of view, disturbances in the concentration of neurotransmitters in the body result in the occurrence of mental disorders and diseases (such as depression, schizophrenia, Parkinson’s disease), contribute to the occurrence of dementia (including Alzheimer’s disease) and others. For this reason, they are used in medicine (e.g., as antidepressants), but they can also be a serious problem in non-medical use (e.g., as a psychoactive substance such as rape pills).

This Special Issue is entitled “Neurotransmitter-Related Molecular Modeling Studies” and aims to bring together research on all aspects of molecular modeling in the neurotransmission phenomenon. It will contain high-quality research articles and review articles summarizing the state-of-the-art in a specific area of this research field.

Prof. Dr. Alicja Nowaczyk
Prof. Dr. Grzegorz Grześk
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Molecular modeling
Structural analysis
Neurotransmitters ligands
Mechanism of action
Synthesis

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Published Papers (10 papers)

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Research

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17 pages, 2294 KiB

Open AccessArticle

Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2

by Magdalena Kowalska, Łukasz Fijałkowski, Monika Kubacka, Kinga Sałat, Grzegorz Grześk, Jacek Nowaczyk and Alicja Nowaczyk

Molecules 2021, 26(12), 3522; https://doi.org/10.3390/molecules26123522 - 9 Jun 2021

Cited by 4 | Viewed by 3083

Abstract

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia—an impairment of cardiac rhythm due to cardiac ion channel dysfunction—is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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17 pages, 35088 KiB

Open AccessArticle

Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

by Aathira Sujathan Nair, Jong-Min Oh, Vishal Payyalot Koyiparambath, Sunil Kumar, Sachithra Thazhathuveedu Sudevan, Opeyemi Soremekun, Mahmoud E. Soliman, Ahmed Khames, Mohamed A. Abdelgawad, Leena K. Pappachen, Bijo Mathew and Hoon Kim

Molecules 2021, 26(11), 3264; https://doi.org/10.3390/molecules26113264 - 28 May 2021

Cited by 12 | Viewed by 4035

Abstract

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC₅₀ value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC₅₀ = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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9 pages, 239 KiB

Open AccessArticle

Cardiometabolic Risk Factors in Rosuvastatin-Treated Men with Mixed Dyslipidemia and Early-Onset Androgenic Alopecia

by Robert Krysiak, Marcin Basiak and Bogusław Okopień

Molecules 2021, 26(10), 2844; https://doi.org/10.3390/molecules26102844 - 11 May 2021

Cited by 10 | Viewed by 2604

Abstract

Men with early-onset androgenetic alopecia are characterized by hormonal profiles similar to those observed in women with polycystic ovary syndrome. The purpose of this research was to investigate levels of cardiometabolic risk factors in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-treated men with early-onset androgenic alopecia. We studied two matched rosuvastatin-treated groups of men with mixed dyslipidemia: subjects with early-onset androgenic alopecia (group A) and subjects with normal hair growth (group B). Plasma lipids, glucose homeostasis markers, and levels of sex hormones, uric acid, hsCRP, homocysteine, fibrinogen, and 25-hydroxyvitamin D were measured before entering the study and six months later. Both groups differed in insulin sensitivity and levels of calculated bioavailable testosterone, dehydroepiandrosterone-sulfate, uric acid, hsCRP, fibrinogen, and 25-hydroxyvitamin D. Though observed in both study groups, treatment-induced reductions in total cholesterol, LDL cholesterol, hsCRP, and fibrinogen were more pronounced in group B than group A. Moreover, only in group A did rosuvastatin deteriorate insulin sensitivity, and only in group B did the drug affect uric acid, homocysteine, and 25-hydroxyvitamin D. The impact of rosuvastatin on cardiometabolic risk factors correlated with insulin sensitivity, calculated bioavailable testosterone, and dehydroepiandrosterone-sulfate. The obtained results suggest that men with early-onset androgenic alopecia may benefit to a lesser degree from rosuvastatin treatment than their peers. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

18 pages, 2128 KiB

Open AccessArticle

Serotonergic Neurotransmission System Modulator, Vortioxetine, and Dopaminergic D₂/D₃ Receptor Agonist, Ropinirole, Attenuate Fibromyalgia-Like Symptoms in Mice

by Kinga Sałat and Anna Furgała-Wojas

Molecules 2021, 26(8), 2398; https://doi.org/10.3390/molecules26082398 - 20 Apr 2021

Cited by 11 | Viewed by 3838

Abstract

Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient’s key symptoms. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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16 pages, 1736 KiB

Open AccessReview

The Role of Serotonin Neurotransmission in Gastrointestinal Tract and Pharmacotherapy

by Tomasz Guzel and Dagmara Mirowska-Guzel

Molecules 2022, 27(5), 1680; https://doi.org/10.3390/molecules27051680 - 3 Mar 2022

Cited by 63 | Viewed by 15059

Abstract

5-Hydroxytryptamine (5-HT, serotonin) is a neurotransmitter in both the central nervous system and peripheral structures, acting also as a hormone in platelets. Although its concentration in the gut covers >90% of all organism resources, serotonin is mainly known as a neurotransmitter that takes part in the pathology of mental diseases. Serotonin modulates not only CNS neurons, but also pain transmission and platelet aggregation. In the periphery, 5-HT influences muscle motility in the gut, bronchi, uterus, and vessels directly and through neurons. Serotonin synthesis starts from hydroxylation of orally delivered tryptophan, followed by decarboxylation. Serotonin acts via numerous types of receptors and clinically plays a role in several neural, mental, and other chronic disorders, such as migraine, carcinoid syndrome, and some dysfunctions of the alimentary system. 5-HT acts as a paracrine hormone and growth factor. 5-HT receptors in both the brain and gut are targets for drugs modifying serotonin neurotransmission. The aim of the present article is to review the 5-HT receptors in the gastrointestinal (GI) tract to determine the role of serotonin in GI physiology and pathology, including known GI diseases and the role of serotonin in GI pharmacotherapy. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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23 pages, 378 KiB

Open AccessReview

Antibiotics and the Nervous System—Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

by Magdalena Hurkacz, Lukasz Dobrek and Anna Wiela-Hojeńska

Molecules 2021, 26(24), 7456; https://doi.org/10.3390/molecules26247456 - 9 Dec 2021

Cited by 26 | Viewed by 5539

Abstract

Antibiotics as antibacterial drugs have saved many lives, but have also become a victim of their own success. Their widespread abuse reduces their anti-infective effectiveness and causes the development of bacterial resistance. Moreover, irrational antibiotic therapy contributes to gastrointestinal dysbiosis, that increases the risk of the development of many diseases, including neurological and psychiatric. One of the potential options for restoring homeostasis is the use of oral antibiotics that are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapy may exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactams and quinolones. Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus or seizures. Their pathomechanism results from the disturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similarities between the structure of the β-lactam ring and GABA molecule) and impairment of the functioning of benzodiazepine receptors (BZD). However, on the other hand, antibiotics have also been studied for their neuroprotective properties in the treatment of neurodegenerative and neuroinflammatory processes (e.g., Alzheimer’s or Parkinson’s diseases). Antibiotics may, therefore, become promising elements of multi-targeted therapy for these entities. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

16 pages, 1706 KiB

Open AccessReview

Neuroprotective Effect of SGLT2 Inhibitors

by Agnieszka Pawlos, Marlena Broncel, Ewelina Woźniak and Paulina Gorzelak-Pabiś

Molecules 2021, 26(23), 7213; https://doi.org/10.3390/molecules26237213 - 28 Nov 2021

Cited by 123 | Viewed by 16558

Abstract

Patients with diabetes are at higher risk of cardiovascular diseases and cognitive impairment. SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Sotagliflozin) are newer hypoglycemic agents with many pleiotropic effects. In this review, we discuss their neuroprotective potential. SGLT2 inhibitors (SGLT2i) are lipid-soluble and reach the brain/serum ratio from 0.3 to 0.5. SGLT receptors are present in the central nervous system (CNS). Flozins are not fully SGLT2-selective and have an affinity for the SGLT1 receptor, which is associated with protection against ischemia/reperfusion brain damage. SGLT2i show an anti-inflammatory and anti-atherosclerotic effect, including reduction of proinflammatory cytokines, M2 macrophage polarization, JAK2/STAT1 and NLRP3 inflammasome inhibition, as well as cIMT regression. They also mitigate oxidative stress. SGLT2i improve endothelial function, prevent remodeling and exert a protective effect on the neurovascular unit, blood-brain barrier, pericytes, astrocytes, microglia, and oligodendrocytes. Flozins are also able to inhibit AChE, which contributes to cognitive improvement. Empagliflozin significantly increases the level of cerebral BDNF, which modulates neurotransmission and ensures growth, survival, and plasticity of neurons. Moreover, they may be able to restore the circadian rhythm of mTOR activation, which is quite a novel finding in the field of research on metabolic diseases and cognitive impairment. SGLT2i have a great potential to protect against atherosclerosis and cognitive impairment in patients with type 2 diabetes mellitus. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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15 pages, 869 KiB

Open AccessReview

Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications

by Grzegorz Grześk and Alicja Nowaczyk

Molecules 2021, 26(11), 3418; https://doi.org/10.3390/molecules26113418 - 4 Jun 2021

Cited by 18 | Viewed by 5740

Abstract

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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19 pages, 1204 KiB

Open AccessReview

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders

by Michał Kosowski, Joanna Smolarczyk-Kosowska, Marcin Hachuła, Mateusz Maligłówka, Marcin Basiak, Grzegorz Machnik, Robert Pudlo and Bogusław Okopień

Molecules 2021, 26(10), 2838; https://doi.org/10.3390/molecules26102838 - 11 May 2021

Cited by 22 | Viewed by 5067

Abstract

Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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20 pages, 1337 KiB

Open AccessFeature PaperReview

Arterial Blood Pressure Variability and Other Vascular Factors Contribution to the Cognitive Decline in Parkinson’s Disease

by Anna Pierzchlińska, Magdalena Kwaśniak-Butowska, Jarosław Sławek, Marek Droździk and Monika Białecka

Molecules 2021, 26(6), 1523; https://doi.org/10.3390/molecules26061523 - 10 Mar 2021

Cited by 10 | Viewed by 3867

Abstract

Dementia is one of the most disabling non-motor symptoms in Parkinson’s disease (PD). Unlike in Alzheimer’s disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures. Full article

(This article belongs to the Special Issue Neurotransmitter-Related Molecular Modeling Studies)

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