Novel models for assessing blood-brain barrier drug permeation.
Humans; Animals; Blood-Brain Barrier/*metabolism; *Capillary Permeability; Drosophila melanogaster/metabolism; Grasshoppers/metabolism; High-Throughput Screening Assays; Pharmaceutical Preparations/*metabolism; Zebrafish/metabolism; Models; Animal
INTRODUCTION: The blood-brain barrier (BBB) is a selectively permeable micro-vascular unit which prevents many central nervous system (CNS)-targeted compounds from reaching the brain. A significant problem in CNS drug development is the ability to model BBB permeability in a timely, reproducible and cost-effective manner. Through the years, several models have been used such as artificial membranes, cell culture and animal models. AREAS COVERED: In this focused review, the authors cover novel models which have been developed or are in the process of being developed which can be used in modeling BBB. These models can either be used to determine BBB permeability or whether a compound may be disrupting the BBB. Many of these models lend themselves to high-throughput screening. The main model organisms covered here are the grasshopper (Locusta migratoria), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio). EXPERT OPINION: Many of the models covered here have only recently been utilized for BBB studies and still needs to be fully studied for its impact on reducing costs during drug development. The strength of these models lay in the fact that a whole organism experiment can be done in high throughput fashion as compared with classical vertebrate models such as micro-dialysis.
Geldenhuys Werner J; Allen David D; Bloomquist Jeffrey R
Expert opinion on drug metabolism & toxicology
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17425255.2012.677433" target="_blank" rel="noreferrer noopener">10.1517/17425255.2012.677433</a>
Novel multifunctional anti-Alzheimer drugs with various CNS neurotransmitter targets and neuroprotective moieties.
Humans; Animals; Drug Design; Alzheimer Disease/pathology/*prevention & control; Central Nervous System/chemistry/*drug effects/metabolism; Neuroprotective Agents/*chemistry/pharmacology/*therapeutic use; Neurotransmitter Agents/chemistry/*metabolism; Biological; Models
Traditionally, drug design programs are focused on optimizing the specificity of lead compounds against a carefully selected drug target. Disappointingly, this approach to discover a "magic bullet" drug has not met with the expected success for CNS disorders. Transcriptomics and proteomic profiling of neurodegenerative diseases have indicated that they are poly-etiological in origin and that the processes leading to neuronal death are multifactorial. An emerging concept is the design of drug ligands that modulate multiple drug targets identified for a particular disease. In this review we explore some examples of multifunctional drugs which may be useful in the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
Van der Schyf Cornelis J; Mandel Silvia; Geldenhuys Werner J; Amit Tamar; Avramovich Yael; Zheng Hailin; Fridkin Mati; Gal Shunit; Weinreb Orly; Bar Am Orit; Sagi Yotam; Youdim Moussa B H
Current Alzheimer research
2007
2007-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/156720507783018226" target="_blank" rel="noreferrer noopener">10.2174/156720507783018226</a>
Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress.
Animals; Cardiac/cytology/*drug effects; Cell Differentiation/drug effects; Flow Cytometry; Knockout; Male; Mice; Mitochondrial Membranes/metabolism; Mitochondrial Proteins/metabolism; Myocytes; Oxidative Stress/drug effects/*physiology; Rats; Real-Time Polymerase Chain Reaction; Stem Cells/cytology/*drug effects; Thiazolidinediones/*pharmacology; Zucker
Ischemic heart disease (IHD) is a leading cause of death worldwide, and regenerative therapies through exogenous stem cell delivery hold promising potential. One limitation of such therapies is the vulnerability of stem cells to the oxidative environment associated with IHD. Accordingly, manipulation of stem cell mitochondrial metabolism may be an effective strategy to improve survival of stem cells under oxidative stress. MitoNEET is a redox-sensitive, mitochondrial target of thiazolidinediones (TZDs), and influences cellular oxidative capacity. Pharmacological targeting of mitoNEET with the novel TZD, mitoNEET Ligand-1 (NL-1), improved cardiac stem cell (CSC) survival compared to vehicle (0.1% DMSO) during in vitro oxidative stress (H2O2). 10 muM NL-1 also reduced CSC maximal oxygen consumption rate (OCR) compared to vehicle. Following treatment with dexamethasone, CSC maximal OCR increased compared to baseline, but NL-1 prevented this effect. Smooth muscle alpha-actin expression increased significantly in CSC following differentiation compared to baseline, irrespective of NL-1 treatment. When CSCs were treated with glucose oxidase for 7 days, NL-1 significantly improved cell survival compared to vehicle (trypan blue exclusion). NL-1 treatment of cells isolated from mitoNEET knockout mice did not increase CSC survival with H2O2 treatment. Following intramyocardial injection of CSCs into Zucker obese fatty rats, NL-1 significantly improved CSC survival after 24 h, but not after 10 days. These data suggest that pharmacological targeting of mitoNEET with TZDs may acutely protect stem cells following transplantation into an oxidative environment. Continued treatment or manipulation of mitochondrial metabolism may be necessary to produce long-term benefits related to stem cell therapies.
Logan Suzanna J; Yin Liya; Geldenhuys Werner J; Enrick Molly K; Stevanov Kelly M; Carroll Richard T; Ohanyan Vahagn A; Kolz Christopher L; Chilian William M
Basic research in cardiology
2015
2015-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-015-0471-z" target="_blank" rel="noreferrer noopener">10.1007/s00395-015-0471-z</a>
Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling.
*MAP Kinase Signaling System; *Signal Transduction; Animals; Cell Differentiation; Cells; Cultured; Eye Proteins/*metabolism; Hyaluronan Receptors/*metabolism; Inbred C57BL; Male; Membrane Glycoproteins/*metabolism; Mice; Osteoclasts/*cytology/metabolism; RANK Ligand/metabolism; Recombinant Proteins/metabolism
Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteolysis in vivo. Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation.
Sondag Gregory R; Mbimba Thomas S; Moussa Fouad M; Novak Kimberly; Yu Bing; Jaber Fatima A; Abdelmagid Samir M; Geldenhuys Werner J; Safadi Fayez F
Experimental & molecular medicine
2016
2016-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/emm.2016.78" target="_blank" rel="noreferrer noopener">10.1038/emm.2016.78</a>
Oxidative stress and Alzheimer's disease: dietary polyphenols as potential therapeutic agents.
Humans; Animals; Oxidative Stress/drug effects/*physiology; Alzheimer Disease/*physiopathology/*therapy; Antioxidants/*administration & dosage/chemistry/pharmacology; Flavonoids/*administration & dosage/chemistry/pharmacology; Mitochondria/drug effects/physiology; Neurodegenerative Diseases/physiopathology; Phenols/*administration & dosage/chemistry/pharmacology; Polyphenols
Oxidative stress has been strongly implicated in the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). In recent years, antioxidants - especially those of dietary origin - have been suggested as possible agents useful for the prevention and treatment of AD. This article reviews the role of oxidative stress and the contribution of free radicals in the development of AD, and also discusses the use of antioxidants as a therapeutic strategy in the amelioration of this illness. The antioxidant potential of polyphenolic compounds obtained from dietary sources, such as anthocyanins from berries, catechins and theaflavins from tea, curcumin from turmeric, resveratrol from grapes and peanuts, the dihydrochalcones aspalathin and nothofagin from rooibos and the xanthone mangiferin from honeybush, are discussed in this review. The neuroprotective effects of these phytochemicals in preclinical models of AD are highlighted. Finally, innovative concepts, novel hypotheses, current challenges and future directions in the use of dietary polyphenols for the treatment of AD are discussed.
Darvesh Altaf S; Carroll Richard T; Bishayee Anupam; Geldenhuys Werner J; Van der Schyf Cornelis J
Expert review of neurotherapeutics
2010
2010-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1586/ern.10.42" target="_blank" rel="noreferrer noopener">10.1586/ern.10.42</a>
Parkinson's disease biomarker: a patent evaluation of WO2013153386.
Humans; Disease Progression; Biomarkers/metabolism; Phosphorylation; Mitochondria/pathology; mitophagy; autophagy; clinical testing; Dopaminergic Neurons/pathology; mitochondrial membrane potential; Parkinson Disease/*diagnosis/physiopathology; Patents as Topic; Protein Kinases/*metabolism; Ubiquitin-Protein Ligases/*metabolism
INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative movement disorder resultant from the loss of dopaminergic neurons in the brain. There is an urgent need for effective biomarkers that can be used in the early diagnosis of PD. Mitochondrial dysfunction plays a significant role in PD pathology, which has led to the evaluation of mitophagy markers, PTEN-induced putative kinase 1 (PINK1), and PARKIN as possible biomarkers for the early diagnosis of PD. AREAS COVERED: The current patent describes the use of phosphorylation of PINK1 and PARKIN as a diagnostic measure. Specifically, Ser65 on PARKIN, which is phosphorylated by PINK1, and the autophosphorylation of PINK1 at Thr257 are described. EXPERT OPINION: This patent describes a much needed methodology that can easily be adapted in the clinical setting by which a biological sample, such as serum or cerebrospinal fluid, is collected and analyzed for the phosphorylation markers. Here, the phosphorylation activity seen in PINK1 and PARKIN can differentiate between age-matched controls and PD patients. This patent presents a novel diagnostic measure in early PD, as well as determines which medications would have a beneficial effect on a patient's disease progression.
Geldenhuys Werner J; Abdelmagid Samir M; Gallegos Patrick J; Safadi Fayez F
Expert opinion on therapeutic patents
2014
2014-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/13543776.2014.931375" target="_blank" rel="noreferrer noopener">10.1517/13543776.2014.931375</a>
Pharmacotherapy of Alzheimer's disease: current and future trends.
Humans; Alzheimer's disease; Alzheimer Disease/*drug therapy; anti-inflammatory agents; antioxidants; cholinesterase inhibitors; dementia; Drug Therapy/*methods/*trends; immunotherapy; memantine; multi-targeted drugs; natural products; pharmacotherapy
Alzheimer's disease (AD) and its related dementia has shown an alarming rise in the global population. Although considerable efforts have been made to develop effective therapeutic agents for AD therapy, drug development has not met significant clinical success. Current pharmacotherapy of AD is limited to cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine. Considerable research is underway to develop newer agents for the management of AD. Since amyloid-beta (Abeta) has been implicated in AD pathogenesis, the use of beta secretase inhibitors as well as immunotherapy against Abeta has been investigated. A considerable effort has been spent investigating the therapeutic potential of antioxidants and anti-inflammatory agents, several of natural products and dietary origin, in AD treatment. Numerous drug targets have also been investigated for AD treatment and a modest drug pipeline is available. Despite these efforts, drug development for AD has proved extremely difficult and most clinical trials have afforded disappointing results.
Geldenhuys Werner J; Darvesh Altaf S
Expert review of neurotherapeutics
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1586/14737175.2015.990884" target="_blank" rel="noreferrer noopener">10.1586/14737175.2015.990884</a>
Polycyclic compounds: ideal drug scaffolds for the design of multiple mechanism drugs?
*Drug Design; Adamantane/chemistry/pharmacology; Animals; Central Nervous System Diseases/*drug therapy; Humans; Molecular Structure; Neuroprotective Agents/chemistry/*pharmacology/therapeutic use; Polycyclic Compounds/*chemistry/pharmacology/therapeutic use; Psychotropic Drugs/chemistry/*pharmacology/therapeutic use; Quantitative Structure-Activity Relationship
Recently there has been a resurging interest in developing multi-functional drugs to treat diseases with complex pathological mechanisms. Such drug molecules simultaneously target multiple etiologies that have been found to be important modulators in specific diseases. This approach has significant promise and may be more effective than using one compound specific for one drug target or, by a polypharmaceutical approach, using a cocktail of two or more drugs. Polycyclic ring structures are useful as starting scaffolds in medicinal chemistry programs to develop multi-functional drugs, and may also be useful moieties added to existing structures to improve the pharmacokinetic properties of drugs currently used in the clinic or under development. This review attempts to provide a synopsis of current published research to exemplify the use of polycyclic compounds as starting molecules to develop multi-functional drugs.
Van der Schyf Cornelis J; Geldenhuys Werner J
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
2009
2009-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.nurt.2008.10.037" target="_blank" rel="noreferrer noopener">10.1016/j.nurt.2008.10.037</a>
Primary cilia regulates the directional migration and barrier integrity of endothelial cells through the modulation of hsp27 dependent actin cytoskeletal organization.
*Cell Movement; Actin Cytoskeleton/*metabolism; Animals; Blotting; Capillary Permeability/*physiology; Cell Adhesion; Cilia/metabolism; Endothelial Cells/cytology/*metabolism; Fluorescent Antibody Technique; Focal Adhesions/metabolism; HSP27 Heat-Shock Proteins/*metabolism; Mice; Polycystic Kidney Diseases/physiopathology; Signal Transduction/physiology; Transgenic; Western
Cilia are mechanosensing organelles that communicate extracellular signals into intracellular responses. Altered functions of primary cilia play a key role in the development of various diseases including polycystic kidney disease. Here, we show that endothelial cells from the oak ridge polycystic kidney (Tg737(orpk/orpk) ) mouse, with impaired cilia assembly, exhibit a reduction in the actin stress fibers and focal adhesions compared to wild-type (WT). In contrast, endothelial cells from polycystin-1 deficient mice (pkd1(null/null) ), with impaired cilia function, display robust stress fibers, and focal adhesion assembly. We found that the Tg737(orpk/orpk) cells exhibit impaired directional migration and endothelial cell monolayer permeability compared to the WT and pkd1(null/null) cells. Finally, we found that the expression of heat shock protein 27 (hsp27) and the phosphorylation of focal adhesion kinase (FAK) are downregulated in the Tg737(orpk/orpk) cells and overexpression of hsp27 restored both FAK phosphorylation and cell migration. Taken together, these results demonstrate that disruption of the primary cilia structure or function compromises the endothelium through the suppression of hsp27 dependent actin organization and focal adhesion formation, which may contribute to the vascular dysfunction in ciliopathies.
Jones Thomas J; Adapala Ravi K; Geldenhuys Werner J; Bursley Chris; AbouAlaiwi Wissam A; Nauli Surya M; Thodeti Charles K
Journal of cellular physiology
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jcp.22704" target="_blank" rel="noreferrer noopener">10.1002/jcp.22704</a>
Role of serotonin in Alzheimer's disease: a new therapeutic target?
Humans; Animals; Serotonin/*metabolism; Clinical Trials as Topic; Alzheimer Disease/*drug therapy/*metabolism; Serotonin/*pharmacology/*therapeutic use; Clinical Trials; Receptors; Drug Evaluation; Preclinical; Alzheimer's Disease – Drug Therapy; Alzheimer's Disease – Metabolism; Cell Surface – Metabolism; Serotonin – Pharmacodynamics; Serotonin – Therapeutic Use
Mounting evidence accumulated over the past few years indicates that the neurotransmitter serotonin plays a significant role in cognition. As a drug target, serotonin receptors have received notable attention due in particular to the role of several serotonin-receptor subclasses in cognition and memory. The intimate anatomical and neurochemical association of the serotonergic system with brain areas that regulate memory and learning has directed current drug discovery programmes to focus on this system as a major therapeutic drug target. Thus far, none of these programmes has yielded unambiguous data that suggest that any of the new drug entities possesses disease-modifying properties, and significantly more research in this promising area of investigation is required. Compounds are currently being investigated for activity against serotonin 5-HT(1), 5-HT(4) and
Geldenhuys Werner J; Van der Schyf Cornelis J
CNS Drugs
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2165/11590190-000000000-00000" target="_blank" rel="noreferrer noopener">10.2165/11590190-000000000-00000</a>
Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway.
Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology; Antitumor; AXL; Cell Line; Cell Proliferation/drug effects; Cell Survival/drug effects; Dose-Response Relationship; Drug; Drug Resistance; Drug Screening Assays; Gallium; Gallium-resistance; Gallium/pharmacology; Humans; Lung cancer; Lung Neoplasms/drug therapy/*enzymology/*pathology; Molecular Structure; Naphthalenes/chemistry/*pharmacology; Neoplasm/drug effects; Proto-Oncogene Proteins/*antagonists & inhibitors/metabolism; Pyrazoles/chemistry/*pharmacology; Quinolines/chemistry/*pharmacology; Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism; Structure-Activity Relationship; Tetrazoles/chemistry/*pharmacology; Tumor; Virtual screening
The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC50 values from treating
Oyewumi Moses O; Alazizi Adnan; Liva Sophia; Lin Li; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2014
2014-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2014.07.072" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2014.07.072</a>
Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease.
Humans; Molecular Structure; Serotonin/*metabolism; Alzheimer Disease/*drug therapy; Serotonin Antagonists/chemistry/*therapeutic use; Nootropic Agents/chemistry/*therapeutic use; Receptors
Recently, the serotonin 5-HT(6) receptor has been identified as a drug target for attenuating cognitive deficits associated with Alzheimer's disease (AD). Additionally, this receptor may also play a role in schizophrenia, anxiety and obesity. Reports in the literature suggest that the production of selective antagonists for the 5-HT(6) receptor has increased during the last 10 years, with some compounds currently in clinical trials for the treatment of AD. In this review, we will address the rationale for using 5-HT(6) receptor antagonists in AD, as well as report on current advances in the understanding of the structure-activity relationships required to synthesize 5-HT(6) receptor antagonists.
Geldenhuys Werner J; Van der Schyf Cornelis J
Current topics in medicinal chemistry
2008
2008
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/156802608785161420" target="_blank" rel="noreferrer noopener">10.2174/156802608785161420</a>
Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator.
*Diabetes; *High-fat diet; *Homology modeling; *Hyperlipidemia; *Lipoprotein lipase; *Liver cirrhosis; *Obesity; Animals; Benzeneacetamides/chemical synthesis/chemistry/*pharmacology; Dose-Response Relationship; Drug; Imidazoles/chemical synthesis/chemistry/*pharmacology; Lipoprotein Lipase/*metabolism; Mice; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship
Elevated triglycerides (TG) contribute towards increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is an enzyme that is responsible for the metabolism of core triglycerides of very-low density lipoproteins (VLDL) and chylomicrons in the vasculature. In this study, we explored the structure-activity relationships of our lead compound (C10d) that we have previously identified as an LPL agonist. We found that the cyclopropyl moiety of C10d is not absolutely necessary for LPL activity. Several substitutions were found to result in loss of LPL activity. The compound C10d was also tested in vivo for its lipid lowering activity. Mice were fed a high-fat diet (HFD) for four months, and treated for one week at 10mg/kg. At this dose, C10d exhibited in vivo biological activity as indicated by lower TG and cholesterol levels as well as reduced body fat content as determined by ECHO-MRI. Furthermore, C10d also reduced the HFD induced fat accumulation in the liver. Our study has provided insights into the structural and functional characteristics of this novel LPL activator.
Geldenhuys Werner J; Caporoso Joel; Leeper Thomas C; Lee Yoon-Kwang; Lin Li; Darvesh Altaf S; Sadana Prabodh
Bioorganic & medicinal chemistry letters
2017
2017-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2016.11.053" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2016.11.053</a>
Structure-activity relationship and docking studies of thiazolidinedione-type compounds with monoamine oxidase B.
Animals; Humans; Inbred C57BL; Male; Mice; Models; Molecular; Molecular Structure; Monoamine Oxidase Inhibitors/chemical synthesis/chemistry/*pharmacology; Monoamine Oxidase/*metabolism; Stereoisomerism; Structure-Activity Relationship; Thiazolidinediones/chemical synthesis/chemistry/*pharmacology
The neuroprotective activity of pioglitazone and rosiglitazone in the MPTP parkinsonian mouse prompted us to evaluate a set of thiazolidinedione (TZD) type compounds for monoamine oxidase A and B inhibition activity. These compounds were able to inhibit MAO-B over several log units of magnitude (82 nM to 600 muM). Initial structure-activity relationship studies identified key areas to modify the aromatic substituted TZD compounds. Primarily, substitutions on the aromatic group and the TZD nitrogen were key areas where activity was enhanced within this group of compounds.
Carroll Richard T; Dluzen Dean E; Stinnett Hilary; Awale Prabha S; Funk Max O; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2011.06.060" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2011.06.060</a>
Structure-activity relationships of pentacycloundecylamines at the
Amines/chemical synthesis/chemistry/*pharmacology; Animals; Brain/drug effects; Dizocilpine Maleate/pharmacology; Excitatory Amino Acid Antagonists/*pharmacology; Inbred ICR; Ion Channels; Male; Mice; Models; Molecular; N-Methyl-D-Aspartate/*antagonists & inhibitors; Phencyclidine/analogs & derivatives; Piperidines/pharmacology; Radioligand Assay; Receptors; Structure-Activity Relationship; Synaptosomes/*drug effects; Thiophenes/pharmacology
Prompted by our interest in neuroprotective agents with multiple mechanisms of action, we assessed the structure-activity relationship of a series of pentacycloundecylamine derivatives previously shown to have both L-type calcium channel blocking activity and N-methyl-d-aspartate receptor (NMDAR) antagonistic activity. We utilized a functional assay to measure NMDAR channel block using (45)Ca(2+) influx into synaptoneurosomes. The cage amine
Geldenhuys Werner J; Malan Sarel F; Bloomquist Jeffrey R; Van der Schyf Cornelis J
Bioorganic & medicinal chemistry
2007
2007-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmc.2006.09.060" target="_blank" rel="noreferrer noopener">10.1016/j.bmc.2006.09.060</a>
Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET.
*Drug Design; Animals; Binding Sites/drug effects/physiology; Dose-Response Relationship; Drug; Drug Delivery Systems/*methods; Liver/drug effects/metabolism; Mitochondria; Mitochondrial Proteins/*metabolism; Protein Structure; Rats; Secondary; Structure-Activity Relationship; Thiazolidinediones/administration & dosage/*chemical synthesis/*metabolism
Several PPAR-gamma agonists containing a thiazolidinedione moiety (referred to as glitazones) have been proposed to be neuroprotective and appear to alter mitochondrial function. Recently, a search for mitochondrial proteins that bind pioglitazone identified a novel protein, mitoNEET, which was later shown to regulate the oxidative capacity of the mitochondria. This identified an alternative target for the glitazones suggesting a possible new drug target for the treatment of neurodegenerative diseases. Molecular docking studies employing the reported crystal structure revealed five possible binding pockets on mitoNEET. We focused on two sites based on their physical characteristics. Using binding information gained from the analysis of two glitazones docked in these pockets, we designed and synthesized a ligand (NL-1) that would preferentially bind to site 1. Based on [(3)H]-binding data of the glitazones and comparisons to computer generated K(i)s, we were able to predict that site 1 was likely the target of the glitazones. NL-1 uncoupled isolated mitochondrial complex I respiration with an IC(50) of 2.4 microM and inhibited state III respiration up to 45%. To investigate the ability of NL-1 to block rotenone initiated free radicals from complex I, we found it was able to protect the human neuronal cell line SH-SY5Y against rotenone induced cell death. These data demonstrate that mitoNEET is a viable target for the design and synthesis of novel therapeutic agents aimed at altering mitochondrial function.
Geldenhuys Werner J; Funk Max O; Barnes Kendra F; Carroll Richard T
Bioorganic & medicinal chemistry letters
2010
2010-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2009.12.088" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2009.12.088</a>
Synthesis and Biological Evaluation of Pentacycloundecylamines and Triquinylamines as Voltage-Gated Calcium Channel Blockers.
Alicyclic/chemical synthesis/*chemistry/pharmacology; Amines/chemical synthesis/*chemistry/pharmacology; Animals; Apoptosis/drug effects; Calcium Channel Blockers/chemical synthesis/*chemistry/pharmacology; Calcium Channels; Calcium/*metabolism; Cell Survival/drug effects; Hydrocarbons; Hydrogen Peroxide/pharmacology; L-Lactate Dehydrogenase/metabolism; L-type calcium channel (LTCC) blockers; L-Type/*metabolism; Multifunctional drugs; Neurodegeneration; PC12 Cells; Pentacycloundecylamine; Quinones/chemical synthesis/*chemistry/pharmacology; Rats; Structure-Activity Relationship; Triquinylamine
Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca(2+) overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca(2+) overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall,
Young Lois-May; Geldenhuys Werner J; Domingo Olwen C; Malan Sarel F; Van der Schyf Cornelis J
Archiv der Pharmazie
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/ardp.201500293" target="_blank" rel="noreferrer noopener">10.1002/ardp.201500293</a>
The blood-brain barrier choline transporter.
Humans; Animals; Drug Delivery Systems/*methods; Blood-Brain Barrier/drug effects/*metabolism; Membrane Transport Proteins/*metabolism; Organic Cation Transport Proteins/metabolism; Organic Cation Transporter 1/metabolism; Organic Cation Transporter 2
Drug delivery to the brain is made difficult by the blood-brain barrier (BBB) which is selectively permeable to organic drug compounds. Several membrane solute and nutrient transporters are expressed in the BBB vasculature, which may be utilized as mechanism of delivery of drugs to the brain. Of interest to us, are the organic cation transporters which could be used to transport cationic compounds into the CNS. In this mini-review, we will review the current understanding of the structural requirements for designing compounds which could effectively use organic cation transporters (OCT). For the first time, structural requirements for both OCT1 and OCT2 versus the BBB choline transporter (BBBCHT) are discussed and compared. The information gained here could increase the success rate in successful CNS drug delivery and therapeutics.
Geldenhuys Werner J; Allen David D
Central nervous system agents in medicinal chemistry
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/187152412800792670" target="_blank" rel="noreferrer noopener">10.2174/187152412800792670</a>
The emergence of designed multiple ligands for neurodegenerative disorders.
*Drug Design; *Ligands; Amyloid beta-Peptides/metabolism; Antiparkinson Agents/therapeutic use; Clinical Trials as Topic; Humans; Molecular Structure; Neurodegenerative Diseases/*drug therapy; Neuroprotective Agents/*therapeutic use
The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target. A recent trend in drug design and discovery is the rational design or serendipitous discovery of novel drug entities with the ability to address multiple drug targets that form part of the complex pathophysiology of a particular disease state. In this review we discuss the rationale for developing such multifunctional drugs (also called designed multiple ligands or DMLs), and why these drug candidates seem to offer better outcomes in many cases compared to single-targeted drugs in pre-clinical studies for neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Examples are drawn from the literature of drug candidates that have already reached the market, some unsuccessful attempts, and others that are still in the drug development pipeline.
Geldenhuys Werner J; Youdim Moussa B H; Carroll Richard T; Van der Schyf Cornelis J
Progress in neurobiology
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.pneurobio.2011.04.010" target="_blank" rel="noreferrer noopener">10.1016/j.pneurobio.2011.04.010</a>
The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease.
Humans; Animals; Structure-Activity Relationship; Serotonin/*metabolism; Drug Design; Alzheimer Disease/*complications; Cognition Disorders/*drug therapy/*etiology; Serotonin Antagonists/chemistry/*therapeutic use; Receptors; Biological; Models
The serotonin 6 receptor is attracting attention as an etiological contributor in cognition deficits in diseases such as Alzheimer's disease, anxiety/depression and schizophrenia. In this review, we discuss the role of this recently discovered G protein-coupled receptor in cognition and memory, particularly in Alzheimer's disease. A surge in publications that describe the development of ligands for this receptor have recently come to light, underscoring the emerging interest in this receptor as a drug target. We also explore the current status of structure-activity relationship studies that have focused on the design of novel antagonists for the serotonin 6 receptor.
Geldenhuys Werner J; Van der Schyf Cornelis J
Expert review of neurotherapeutics
2009
2009-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1586/ern.09.51" target="_blank" rel="noreferrer noopener">10.1586/ern.09.51</a>
Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.
*Models; *Narcotic Antagonists; *Quantitative Structure-Activity Relationship; Animals; Binding; Calcium Signaling/drug effects; CHO Cells; Competitive; Cricetinae; Cricetulus; Databases; Factual; Humans; Ligands; Molecular; Neurokinin-3/*antagonists & inhibitors/chemistry; Opioid/chemistry; Quinolines/*chemistry/pharmacology; Radioligand Assay; Receptors
The NK(3) subtype of tachykinin receptor is a G protein-coupled receptor that is a potential therapeutic target for several neurological diseases, including schizophrenia. In this study, we have screened compound databases for novel NK(3) receptor antagonists using a virtual screening protocol of similarity analysis. The lead compound for this study was the potent NK(3) antagonist talnetant. Compounds of the quinoline type found in the virtual screen were additionally evaluated in a comparative molecular field analysis model to predict activity a priori to testing in vitro. Selected members of this latter set were tested for their ability to inhibit ligand binding to the NK(3) receptor as well as to inhibit senktide-induced calcium responses in cells expressing the human NK(3) receptor. Two novel compounds were identified that inhibited NK(3) receptor agonist binding, with potencies in the nM range and antagonized NK(3) receptor-mediated increases in intracellular calcium. These results demonstrate the utility of similarity analysis in identifying novel antagonist ligands for neuropeptide receptors.
Geldenhuys Werner J; Kuzenko Stephanie R; Simmons Mark A
Journal of medicinal chemistry
2010
2010-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/jm1010012" target="_blank" rel="noreferrer noopener">10.1021/jm1010012</a>