Central Nervous System Drug Development Research Articles

A method to predict different mechanisms for blood-brain barrier permeability of CNS activity compounds in Chinese herbs using support vector machine.

The blood-brain barrier (BBB), a highly selective barrier between central nervous system (CNS) and the blood stream, restricts and regulates the penetration of compounds from the blood into the brain. Drugs that affect the CNS interact with the BBB prior to their target site, so the prediction research on BBB permeability is a fundamental and significant research direction in neuropharmacology. In this study, we combed through the available data and then with the help of support vector machine (SVM), we established an experiment process for discovering potential CNS compounds and investigating the mechanisms of BBB permeability of them to advance the research in this field four types of prediction models, referring to CNS activity, BBB permeability, passive diffusion and efflux transport, were obtained in the experiment process. The first two models were used to discover compounds which may have CNS activity and also cross the BBB at the same time; the latter two were used to elucidate the mechanism of BBB permeability of those compounds. Three optimization parameter methods, Grid Search, Genetic Algorithm (GA), and Particle Swarm Optimization (PSO), were used to optimize the SVM models. Then, four optimal models were selected with excellent evaluation indexes (the accuracy, sensitivity and specificity of each model were all above 85%). Furthermore, discrimination models were utilized to study the BBB properties of the known CNS activity compounds in Chinese herbs and this may guide the CNS drug development. With the relatively systematic and quick approach, the application rationality of traditional Chinese medicines for treating nervous system disease in the clinical practice will be improved.

Establishment of a Human Neuronal Network Assessment System by Using a Human Neuron/Astrocyte Co-Culture Derived from Fetal Neural Stem/Progenitor Cells

Using human cell models mimicking the central nervous system (CNS) provides a better understanding of the human CNS, and it is a key strategy to improve success rates in CNS drug development. In the CNS, neurons function as networks in which astrocytes play important roles. Thus, an assessment system of neuronal network functions in a co-culture of human neurons and astrocytes has potential to accelerate CNS drug development. We previously demonstrated that human hippocampus-derived neural stem/progenitor cells (HIP-009 cells) were a novel tool to obtain human neurons and astrocytes in the same culture. In this study, we applied HIP-009 cells to a multielectrode array (MEA) system to detect neuronal signals as neuronal network functions. We observed spontaneous firings of HIP-009 neurons, and validated functional formation of neuronal networks pharmacologically. By using this assay system, we investigated effects of several reference compounds, including agonists and antagonists of glutamate and γ-aminobutyric acid receptors, and sodium, potassium, and calcium channels, on neuronal network functions using firing and burst numbers, and synchrony as readouts. These results indicate that the HIP-009/MEA assay system is applicable to the pharmacological assessment of drug candidates affecting synaptic functions for CNS drug development.

Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression.

The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit-derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity of the polyethylenimine is eliminated by the GNVs. Intranasal administration of miR17 carried by FA-pGNVs led to rapid delivery of miR17 to the brain that was selectively taken up by GL-26 tumor cells. Mice treated intranasally with FA-pGNV/miR17 had delayed brain tumor growth. Our results demonstrate that this strategy may provide a noninvasive therapeutic approach for treating brain-related disease through intranasal delivery.

The development of lurasidone for bipolar depression.

Bipolar disorder is a chronic, recurrent illness that ranks among the top 10 causes of disability in the developed world. As the illness progresses, major depressive episodes increasingly predominate. However, few treatment options are available that have demonstrated efficacy in the treatment of bipolar depression, either as monotherapy or adjunctive therapy in combination with mood stabilizers. Lurasidone is an atypical antipsychotic drug that was initially developed for the treatment of schizophrenia. Since no previous atypical antipsychotic development program had proceeded directly from work on schizophrenia to bipolar depression, the decision to focus on this indication represented an innovation in central nervous system drug development and was designed to address a clinically significant unmet need. The current review summarizes key results of a clinical development program undertaken to characterize the efficacy and safety of lurasidone in patients diagnosed with bipolar depression. Lurasidone is currently the only treatment for bipolar depression approved in the United States as both a monotherapy and an adjunctive therapy with lithium or valproate. The approval of lurasidone expands available treatment options for patients with bipolar depression and provides a therapy with an overall favorable risk-benefit profile.

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.

Therapeutic Potential of 5-HT6 Receptor Agonists

Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox.

Personalized medicine for pathological circadian dysfunctions.

The recent approval of a therapeutic for a circadian disorder has increased interest in developing additional medicines for disorders characterized by circadian disruption. However, previous experience demonstrates that drug development for central nervous system (CNS) disorders has a high failure rate. Personalized medicine, or the approach to identifying the right treatment for the right patient, has recently become the standard for drug development in the oncology field. In addition to utilizing Companion Diagnostics (CDx) that identify specific genetic biomarkers to prescribe certain targeted therapies, patient profiling is regularly used to enrich for a responsive patient population during clinical trials, resulting in fewer patients required for statistical significance and a higher rate of success for demonstrating efficacy and hence receiving approval for the drug. This personalized medicine approach may be one mechanism that could reduce the high clinical trial failure rate in the development of CNS drugs. This review will discuss current circadian trials, the history of personalized medicine in oncology, lessons learned from a recently approved circadian therapeutic, and how personalized medicine can be tailored for use in future clinical trials for circadian disorders to ultimately lead to the approval of more therapeutics for patients suffering from circadian abnormalities.

Optimizing Central Nervous System Drug Development Using Molecular Imaging.

Advances in multimodality fusion imaging technologies promise to accelerate the understanding of the systems biology of disease and help in the development of new therapeutics. The use of molecular imaging biomarkers has been proven to shorten cycle times for central nervous system (CNS) drug development and thereby increase the efficiency and return on investment from research. Imaging biomarkers can be used to help select the molecules, doses, and patients most likely to test therapeutic hypotheses by stopping those that have little chance of success and accelerating those with potential to achieve beneficial clinical outcomes. CNS imaging biomarkers have the potential to drive new medical care practices for patients in the latent phases of progressive neurodegenerative disorders by enabling the detection, preventative treatment, and tracking of disease in a paradigm shift from today's approaches that have to see the overt symptoms of disease before treating it.

Unraveling binding interactions of serotonin 5‐HT1B/1D receptor agonists on P‐glycoprotein: the gatekeeper of the brain

Lack of drug penetration through the blood‐brain barrier (BBB) represents a formidable hurdle to treatment of central nervous system (CNS) diseases and the development of CNS drugs. The transporter P‐glycoprotein (Pgp) is the gatekeeper at the BBB and effluxes a wide range of chemically and structurally diverse neurotherapeutics. The triptans represent a chemical class of CNS agonists that show large differences in their Pgp efflux rates and transport properties, despite their similarities in molecular structure. We hypothesize that the variations of chemical structure and P‐glycoprotein transport rate in the triptan class are controlled by differences in the binding location on the transporter. Identifying the molecular features that are critical for transport will improve predictions of drug disposition and will lead to novel neurotherapeutics that have minimal transport. To gain insight into the molecular basis of triptan transport, binding interactions and efflux ratios were characterized within our biomimetic model consisting of reconstituted Pgp in artificial membranes. Specific ATPase activity, transport and intrinsic tryptophan fluorescence were used to investigate eletriptan (Relpax®) and zolmitriptan (Zomig®) binding interactions in our biomimetic model. We have successfully reconstituted Pgp and characterized the ATPase activity and transport with the probe drug verapamil. Eletriptan and zolmitriptan were identified to have different ATPase activity, transport rates and intrinsic tryptophan fluorescence, suggesting these neurotherapeutics interact with Pgp in distinct regions on the transporter.

Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care.

Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21st century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders.Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues,Prevention, early diagnosis, and treatment,Linking science and regulation,Patient involvement in trial design, definition of endpoints, etc.,Novel trial design,Reproduction and confirmation of data,Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority),Large-scale, global patient registries,Editorials on nomenclature, biomarkers, and diagnostic tools, andPublic awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos, Switzerland. In this context Professor Barbara Sahakian recently made a formal presentation at the World Economic Forum (see Barbara Sahakian Blog from April 11, 2014, at https://forumblog.org/people/barbara-sahakian/) Full details of the discussions that formed the bases for these actions are presented in the main body of this document.

AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer.

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

A Physiologically Based Modeling Strategy during Preclinical CNS Drug Development

Physiologically based pharmacokinetic (PBPK) modeling of the central nervous system (CNS) provides the opportunity to predict the relevant drug concentrations at the therapeutic target site during preclinical and clinical development. In order to successfully interpret model results, and to provide confidence in the subsequent human predictions, it is essential that an appropriate model structure is chosen at the preclinical stage which takes into account both physiological and drug-specific knowledge. However, the models published to date in the literature show significant variation in the approaches applied by different authors, which can lead to difficulties in the interpretation of model parameter estimates. We aimed to develop a coherent PBPK modeling approach in the rat, which would also be adaptable depending on the quantity and quality of in vivo data obtained during drug development. Based on a sensitivity analysis of the model parameters, and using three CNS drugs as case studies (atomoxetine, acetaminophen, and S 18986), we proposed a decision tree to aid in the appropriate parametrization and structure of the model according to the data available. We compared our parameter estimates to those originally published, and considered the impact of the respective approaches on the mechanistic interpretation of the parameter values. Since the measurement of brain extracellular fluid (ECF) concentrations using microdialysis is not routinely performed in the industrial environment, we also evaluated the bottom-up scaling of in vitro permeability data from the Caco-2 cell line to predict BBB passive permeability in the absence of measured ECF concentrations. Our strategy demonstrates the value of PBPK as a prediction tool throughout the development process of CNS-targeting drugs.

Evaluation of <i>Abelmoschus moschatus</i> seed extract in psychiatric and neurological disorders

Background: Abelmoschus moschatus is an aromatic and medicinal plant, used as traditional medicine in the Thirunelveli district and distributed in many parts of Asia, including India. The present study was aimed to evaluate central nervous system (CNS) activities of ethanolic seed extract of A. moschatus (AEAM). Methods: Oral administration of AEAM at doses of 200 and 400 mg/kg on various behavioral models forced swim, tail suspension, light-dark box, hole-board, elevated-plus-maze, locomotor, strychnine, maximal electroshock induced seizure, pentylenetetrazole (PTZ), rotarod, climbing an inclined screen models were utilized. Results: In the open field test, AEAM (200 and 400 mg/kg) increased the numbers of rearing. However, the number of central motor and ambulation were reduced. The number of entries and the time spent in the open arm were increased, whereas the number of locomotion was decreased (p<0.001) in elevated-plus-maze and actophotometer test, respectively. AEAM (200 and 400 mg/kg) protected the mice against the PTZ and strychnine-induced convulsions; it causes significant dose-dependent increase in latency of convulsion. Treatment with AEAM reduced the duration of the tonic hind limb extension, increased the hypnotics time and decreased motor co-ordination of experimental animals. Conclusion: This study concludes A. moschatus is an alternative source for CNS drug development.

Frontiers of Biomolecular Exploration in Brain Disorders

Five volumes of the Neuropsychopharmacology: The Next Generation of Progress were published in print by the American College of Neuropsychopharmacology between the years 1968 and 2002. These volumes historically defined the scientific arena of neuropsychopharmacology and served for 40+ years as major references, providing a foundation of the research and therapeutics knowledge in psychiatric and neurological disorders. With the increasingly fast-paced evolution of our field, the ACNP opted to continue the tradition in the more dynamic format of devoting the first issue of its flagship journal each year to Neuropsychopharmacology Reviews: The Next Generation of Progress. The first six issues have provided outstanding and timely overviews of neuroplasticity (Vol. 1), central nervous system (CNS) drug discovery and development (Vol. 2), neurocircuitry (Vol. 3), cognition (Vol. 4), neurotherapeutics (Vol. 5), and epigenetics (Vol. 6). The seventh issue of Neuropsychopharmacology Reviews is devoted to biomolecular discovery and the implications for mechanisms, therapeutics, and biomarker development. The articles in this issue focus on the recent advances in the detection, subtyping, and monitoring of complex neural disease progression, the definition of new molecular targets for therapeutic intervention and biomarkers, with an emphasis on the use of genome-wide analytical technologies.

The Neuropsychiatric Translational Revolution

Advances in knowledge of mammalian neurobiology and genomics far outpace their application to common but complex human disorders, especially those impacting brain function. Recently, Karayiorgou et al1 argued for the almost exclusive use and funding of neuropsychiatric research using highly penetrant de novo mutations and selected animal models to illuminate the neural circuit and genomic network basis of neuropsychiatric disorders and to get Big Pharma back into central nervous system drug development. While their viewpoint reflects the great speed with which knowledge about mammalian genomics and neurobiology is proceeding, the translation of this kind of new basic science data to the bedside is proceeding at a much slower pace, making such prescriptive scientific pathways premature.2 Many therapeutic advances in medicine are concentrated in accessible tissue disorders, such as coagulopathies and oncology, where diseased tissue can be directly examined and manipulated. But we largely lack such direct approaches for the relatively inaccessible brain with its complex neural circuit imbalances compared with the more discrete mitotic dysfunctions seen in oncology. Furthermore, with an increasing basic science and genomic focus in psychiatric neuroscience, we often overlook treatment advances in the area of cognitive, psychosocial, and health services interventions, either alone or in conjunction with pharmacotherapies.3 To suggest that one translational approach to complex neuropsychiatric disorders be given almost absolute scientific and funding primacy1 is very premature indeed. The gap between basic and applied research is not specific to neuropsychiatry. Indeed, several years ago, Nobel Laureates Goldstein and Brown4 pointed out that “elite” basic science journals present research that is often disarticulated from the practical clinical realities in medicine. They explained why they published more than 30 articles in the Journal of Clinical Investigation: Because the importance of [these] papers went beyond basic science. Editors and readers of elite basic science journals such as Nature, Cell, and Science would have difficulty comprehending the importance of studying fat accumulation in smooth muscle cells and hepatocytes… By publishing in the JCI, we were able to reach a broad audience of medically oriented scientists.4 In fact, both the etiological and therapeutic implications of much published basic neurobiological research remains unclear. For example, the precise genomic etiology of common (≥1% prevalence) yet complex neuropsychiatric disorders continues to elude us. Based on a qualitative questionnaire administered at the 2011 Program and Executive Committees of the American College of Neuropsychopharmacology and Society of Biological Psychiatry, we found that the gap between basic science research and effective treatment—that is, between the bench and bedside—is of growing concern to senior neuropsychiatric thought leaders. Specifically, about 80% of the 60 thought leaders surveyed believe it is either important or essential for them, their colleagues, and students to see more than 30 patients who have the disorder that they are studying. Yet, nearly two-thirds of thought leaders believe that the research in high-impact basic science journals does not reflect this requisite level of knowledge of the actual neuropsychiatric disorders that are being modeled.5 We face some distinct research challenges in neuropsychiatry. A tissue slice of kidney or lungs or liver gives up its functional role quite easy (eg, in the lung, blood and bronchial structures are designed for gas exchange). In contrast, the brain is less accessible and is morphologically and genomically enigmatic and complex. Thus, we respectfully suggest a number of considerations for the field to create a more relevant translational research environment that narrows the gap between the bench and bedside, while broadening research foci.

Use of functional imaging across clinical phases in CNS drug development

The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials.

Establishment of a new conditionally immortalized cell line from human brain microvascular endothelial cells: A promising tool for human blood–brain barrier studies

The blood-brain barrier (BBB) is formed by brain microvascular endothelial cells (BMEC) working together with astrocytes and pericytes, in which tight junctions and various transporters strictly regulate the penetration of diverse compounds into the brain. Clarification of the molecular machinery that provides such regulation using in vitro BBB models has provided important insights into the roles of the BBB in central nervous system (CNS) disorders and CNS drug development. In this study, we succeeded in establishing a new cell line, hereinafter referred to as human BMEC/conditionally immortalized, clone β (HBMEC/ciβ), as part of our ongoing efforts to develop an in vitro human BBB model. Our results showed that HBMEC/ciβ proliferated well. Furthermore, we found that HBMEC/ciβ exhibited the barrier property of restricting small molecule intercellular penetration and possessed effective efflux transporter functions, both of which are essential to a functioning BBB. Because higher temperatures are known to terminate immortalization signals, we specifically examined the effects of higher temperatures on the HBMEC/ciβ differentiation status. The results showed that higher temperatures stimulated HBMEC/ciβ differentiation, marked by morphological alteration and increases in several mRNA levels. To summarize, our data indicates that the newly established HBMEC/ciβ offers a promising tool for use in the development of a practical in vitro human BBB model that could make significant contributions toward understanding the molecular biology of CNS disorders, as well as to CNS drug development. It is also believed that the development of a specific culture method for HBMEC/ciβ will add significant value to the HBMEC/ciβ-based BBB model.

Comments on the working group’s 2012 review of the Program

Comments on the working group’s 2012 review of the Program

The Tachykinergic System as Avenues for Drug Intervention

This review discusses a family of receptors that interact with a family of small peptides that belong to the tachykinin family. The three subtypes of tachykinin receptors follow the following suggested nomenclature: NK1, NK2 and NK3. These receptors belong to the 7-transmembrane, G-protein coupled family. The NK receptor family has been implicated in a wide range of disorders, cancers, inflammation and neural-related diseases. The tachykinin NK receptors and their ligands have been implicated in solid and hematological tumors. Antagonists to NK receptors have been synthesized and some have been tested in preclinical and Phase II clinical studies. However, in order to be effective for treatment, it is imperative to understand the biology of NK receptor family as well as related molecules. One such molecule is HGFIN, also referred as nmb and osteoactivin. HGFIN is particularly relevant since it has been shown to interact with the high affinity ligand of NK1, substance P. This report discusses promising applications for targeting the NK receptors. The discussion proposes potential mechanisms that could occur when substance P interacts with HGFIN as well as the role of HGFIN when antagonists are used to block the NK receptors. This review is relevant for central and peripheral nervous system drug development and cancer targets and also discusses the indications for current patents.

Combining PET Biodistribution and Equilibrium Dialysis Assays to Assess the Free Brain Concentration and BBB Transport of CNS Drugs

The passage of drugs in and out of the brain is controlled by the blood-brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for de-risking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development.