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>
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>
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>
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>
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>
Designing drugs with multi-target activity: the next step in the treatment of neurodegenerative disorders.
Humans; Clinical Trials as Topic; *Drug Design; Central Nervous System Diseases/*drug therapy; Neurodegenerative Diseases/*drug therapy; Neuroprotective Agents/*chemistry/therapeutic use
INTRODUCTION: Neurodegenerative diseases have had devastating effects on patients' quality of life. These complex diseases have several pathways that are affected to initiate cell death. Current therapies, designed to address only a single target, fall short in mitigating or preventing disease progression, and disease-modifying drugs are desperately needed. Over the past several years, a new paradigm has emerged which has as a goal the targeting of multiple disease etiological pathways. Such "multi-targeted designed drugs" (MTDD) have shown great promise in preclinical studies as neuroprotective agents, as well as being able to afford symptomatic relief to blunt the day-to-day burden of these illnesses. AREAS COVERED: In this review, the authors evaluate the use of chemical scaffolds that led themselves exquisitely to the development of MTDDs in central nervous system disorders. Some of the examples discussed have also transitioned into the clinic, which underscores the importance of pursuing drug discovery programs within the multifunctional arena. EXPERT OPINION: Currently, very little can be done to slow the progress of neurodegeneration. The multifaceted profile of neurodegeneration necessitates a change in paradigm toward the design of compounds that address several drug targets simultaneously. With successful compounds in clinical trials as well as compounds moving into the clinic, support is growing and the feasibility of this approach is now becoming recognized. This review shows that several small molecule scaffolds can be successfully utilized to design MTDD compounds with good CNS pharmacokinetics.
Geldenhuys Werner J; Van der Schyf Cornelis J
Expert opinion on drug discovery
2013
2013-02
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/10.1517/17460441.2013.744746" target="_blank" rel="noreferrer noopener">10.1517/17460441.2013.744746</a>
In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery.
INTRODUCTION: Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. AREAS COVERED: In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and as well as psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. EXPERT OPINION: In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases that are currently in demand.
Darvesh Altaf S; Carroll Richard T; Geldenhuys Werner J; Gudelsky Gary A; Klein Jochen; Meshul Charles K; Van der Schyf Cornelis J
Expert opinion on drug discovery
2011
2011-02
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/10.1517/17460441.2011.547189" target="_blank" rel="noreferrer noopener">10.1517/17460441.2011.547189</a>
Curcumin and neurodegenerative diseases: a perspective.
Humans; Animals; Oxidative Stress/drug effects; Neurodegenerative Diseases/*drug therapy/metabolism; Curcumin/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use; Neuroprotective Agents/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use; Drug Evaluation; Preclinical
INTRODUCTION: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). AREAS COVERED: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed. EXPERT OPINION: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.
Darvesh Altaf S; Carroll Richard T; Bishayee Anupam; Novotny Nicholas A; Geldenhuys Werner J; Van der Schyf Cornelis J
Expert opinion on investigational drugs
2012
2012-08
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/10.1517/13543784.2012.693479" target="_blank" rel="noreferrer noopener">10.1517/13543784.2012.693479</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>
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>
Development and validation of an LC-MS/MS method for determination of the L-type voltage-gated calcium channel/NMDA receptor antagonist NGP1-01 in mouse serum.
Animals; Bridged-Ring Compounds/*blood; Calcium Channel Blockers/*blood; Chromatography; LC-MS/MS; Limit of Detection; Liquid/*methods; Mice; Mouse serum; Multifunctional drug; N-Methyl-D-Aspartate/*antagonists & inhibitors; Neuroprotective agent; NGP1-01; Pentacycloundecylamine; Receptors; Reproducibility of Results; Tandem Mass Spectrometry/*methods
NGP1-01 (8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane) is a heterocyclic cage compound with multifunctional calcium channel blocking activity that has been demonstrated to be neuroprotective in several neurodegenerative models. A sensitive internal standard LC-MS/MS method was developed and validated to quantify NGP1-01 in mouse serum. The internal standard (IS) was
Jogiraju Harini; Zhou Xiang; Gobburi Ashta Lakshmi Prasad; Pedada Kiran K; Geldenhuys Werner J; Van der Schyf Cornelis J; Crish Samuel D; Anderson David J
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
2014
2014-07
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/10.1016/j.jchromb.2014.05.048" target="_blank" rel="noreferrer noopener">10.1016/j.jchromb.2014.05.048</a>
3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (sigma1) receptor.
*Quantitative Structure-Activity Relationship; Amines/*chemistry/metabolism; Aza Compounds/chemistry; Binding Sites; Kinetics; Molecular Docking Simulation; Protein Binding; Protein Structure; Receptors; sigma/*chemistry/metabolism; Tertiary
Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (sigma1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) \textgreater0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (sigma1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78muM) and its phenethyl derivative (IC50=1.54muM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(sigma1) receptor.
Geldenhuys Werner J; Novotny Nicholas; Malan Sarel F; Van der Schyf Cornelis J
Bioorganic & medicinal chemistry letters
2013
2013-03
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/10.1016/j.bmcl.2013.01.069" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2013.01.069</a>
Inhibition of monoamine oxidase by derivatives of piperine, an alkaloid from the pepper plant Piper nigrum, for possible use in Parkinson's disease.
Alkaloids/*chemistry/isolation & purification/pharmacology; Animals; Benzodioxoles/*chemistry/isolation & purification/pharmacology; Binding Sites; Blood-Brain Barrier/drug effects; Bovine/metabolism; Cattle; Humans; Hydrogen Bonding; Molecular Docking Simulation; Monoamine Oxidase Inhibitors/*chemistry/isolation & purification/pharmacology; Monoamine Oxidase/*chemistry/metabolism; Parkinson Disease/metabolism/pathology; Piper nigrum/*chemistry; Piperidines/*chemistry/isolation & purification/pharmacology; Polyunsaturated Alkamides/*chemistry/isolation & purification/pharmacology; Protein Binding; Protein Structure; Serum Albumin; Tertiary
A series of compounds related to piperine and antiepilepsirine was screened in a monoamine oxidase A and B assay. Piperine is an alkaloid from the source plant of both black and white pepper grains, Piper nigrum. Piperine has been shown to have a wide range of activity, including MAO inhibitory activity. The z-factor for the screening assay was found to be greater than 0.8 for both assays. Notably, the compounds tested were selective towards MAO-B, with the most potent compound having an IC(50) of 498 nM. To estimate blood-brain barrier (BBB) permeability, we used a PAMPA assay, which suggested that the compounds are likely to penetrate the BBB. A fluorescent bovine serum albumin (BSA) high-throughput screening (HTS) binding assay showed an affinity of 8 muM for piperine, with more modest binding for other test compounds. Taken together, the data described here may be useful in gaining insight towards the design of selective MAO-B inhibitory compounds devoid of MAO-A activity.
Al-Baghdadi Osamah B; Prater Natalie I; Van der Schyf Cornelis J; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2012
2012-12
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/10.1016/j.bmcl.2012.09.056" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2012.09.056</a>
A scaffold hopping approach to identify novel monoamine oxidase B inhibitors.
*Monoamine Oxidase/chemistry/metabolism; Benzofurans/chemistry/pharmacology; Enzyme Activation/drug effects; Flavonoids/chemistry/pharmacology; Humans; Inhibitory Concentration 50; Models; Molecular; Molecular Structure; Monoamine Oxidase Inhibitors/*chemistry/*pharmacology; Protein Binding/drug effects; Small Molecule Libraries; Structure-Activity Relationship
Monoamine oxidase B (MAO-B) inhibitors are used to treat Parkinson's disease. In this study, we searched for novel MAO-B inhibitors using a scaffold hopping approach based on our experience with the thiazolidinedione (TZD) class of compounds as MAO-B inhibitors. Several novel compounds were identified, with potencies in the low nanomolar and low micromolar range. We also found that derivatives of the natural product sulfuretin are potent MAO-A and MAO-B inhibitors.
Geldenhuys Werner J; Funk Max O; Van der Schyf Cornelis J; Carroll Richard T
Bioorganic & medicinal chemistry letters
2012
2012-02
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.2011.12.056" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2011.12.056</a>
Identification of novel monoamine oxidase B inhibitors by structure-based virtual screening.
Models; Molecular; Monoamine Oxidase Inhibitors/chemistry/*pharmacology; Monoamine Oxidase/*drug effects; Structure-Activity Relationship
Parkinson's disease is a severe debilitating neurodegenerative disorder. Recently, it was shown that the peroxisome proliferating-activator receptor-gamma agonist pioglitazone protected mice from
Geldenhuys Werner J; Darvesh Altaf S; Funk Max O; Van der Schyf Cornelis J; Carroll Richard T
Bioorganic & medicinal chemistry letters
2010
2010-09
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.2010.06.128" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2010.06.128</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>
Multimodal drugs and their future for Alzheimer's and Parkinson's disease.
Alzheimer Disease/*drug therapy/*enzymology/prevention & control; Animals; Combined Modality Therapy/*methods; Forecasting; Humans; Monoamine Oxidase Inhibitors/*pharmacology/therapeutic use; Parkinson Disease/*drug therapy/*enzymology/prevention & control
This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds.
Van der Schyf Cornelis J; Geldenhuys Werner J
International review of neurobiology
2011
1905-07
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/10.1016/B978-0-12-386467-3.00006-6" target="_blank" rel="noreferrer noopener">10.1016/B978-0-12-386467-3.00006-6</a>
Methyl Yellow: A Potential Drug Scaffold for Parkinson's Disease.
*MAO-B inhibitor; *methyl yellow; *MPTP mouse model; *Parkinson's disease; *TMRM
Parkinson's disease (PD) is an age-related neurodegenerative disease affecting movement. To date, there are no currently available therapeutic agents which can prevent or slow disease progression. Here, we evaluated an azobenzene derivative, methyl yellow (MY), as a potential drug scaffold for PD; its inhibitory activity toward monoamine oxidase B (MAO-B) as well as drug-like properties were investigated. The inhibitory effect of MY on MAO activity was determined by a MAO enzyme inhibition assay. In addition, the in vitro properties of MY as a drug candidate (e.g., blood-brain barrier (BBB) permeability, serum albumin binding, drug efflux through P-glycoprotein (P-gp), drug metabolism by P450, and mitochondrial toxicity) were examined. In vivo effectiveness of MY was also evaluated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian mouse model. MY selectively inhibited MAO-B in a dose-dependent and reversible manner. MY was BBB-permeable, bound relatively weakly to serum albumin, was an unlikely substrate for both systems of P-gp and P450, and did not cause mitochondrial toxicity. Results from the MPTP Parkinsonian mouse model indicated that, upon treatment with MY, neurotoxicity induced by MPTP was mitigated. Investigations of MY demonstrate its inhibitory activity toward MAO-B, compliant properties for drug consideration, and its neuroprotective capability in the MPTP Parkinsonian mouse model. These data provide insights into potential use, optimization, and new design of azobenzene derivatives for PD treatment.
Geldenhuys Werner J; Kochi Akiko; Lin Li; Sutariya Vijaykumar; Dluzen Dean E; Van der Schyf Cornelis J; Lim Mi Hee
Chembiochem : a European journal of chemical biology
2014
2014-07
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/10.1002/cbic.201300770" target="_blank" rel="noreferrer noopener">10.1002/cbic.201300770</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
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<a href="http://doi.org/10.1002/ardp.201500293" target="_blank" rel="noreferrer noopener">10.1002/ardp.201500293</a>