Showing papers in "Annual Review of Pharmacology and Toxicology in 2009"

Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics

Abstract: Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic a...

Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.

Abstract: Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase cinical trials.

Lipid Mediators in Health and Disease: Enzymes and Receptors as Therapeutic Targets for the Regulation of Immunity and Inflammation

Abstract: Prostaglandins, leukotrienes, platelet-activating factor, lysophosphatidic acid, sphingosine 1-phosphate, and endocannabinoids, collectively referred to as lipid mediators, play pivotal roles in immune regulation and self-defense, and in the maintenance of homeostasis in living systems. They are produced by multistep enzymatic pathways, which are initiated by the de-esterification of membrane phospholipids by phospholipase A2s or sphingo-myelinase. Lipid mediators exert their biological effects by binding to cognate receptors, which are members of the G protein-coupled receptor superfamily. The synthesis of the lipid mediators and subsequent induction of receptor activity is tightly regulated under normal physiological conditions, and enzyme and/or receptor dysfunction can lead to a variety of disease conditions. Thus, the manipulation of lipid mediator signaling, through either enzyme inhibitors or receptor antagonists and agonists, has great potential as a therapeutic approach to disease. In this review, I summarize our current state of knowledge of the synthesis of lipid mediators and the function of their cognate receptors, and discuss the effects of genetic or pharmacological ablation of enzyme or receptor function on various pathophysiological processes.

Akt/GSK3 signaling in the action of psychotropic drugs.

Abstract: Psychotropic drugs acting on monoamine neurotransmission are major pharmacological treatments for neuropsychiatric conditions such as schizophrenia, depression, bipolar disorder, Tourette syndrome, ADHD, and Alzheimer disease. Independent lines of research involving biochemical and behavioral approaches in normal and/or genetically modified mice provide converging evidence for an involvement of the signaling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behavior by dopamine and serotonin (5-HT). These signaling molecules have also received attention for their role in the actions of psychoactive drugs such as antidepressants, antipsychotics, lithium, and other mood stabilizers. Furthermore, investigations of the mechanism by which D2 dopamine receptors regulate Akt/GSK3 signaling strongly support the physiological relevance of a new modality of G protein-coupled receptor (GPCR) signaling involving the multifunctional scaffolding protein beta-arrestin 2. Elucidation of the contribution of multiple signaling pathways to the action of psychotropic drugs may provide a better biological understanding of psychiatric disorders and lead to more efficient therapeutics.

Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology.

Abstract: Cellular proteins are in a dynamic state maintained by synthesis and degradation. The ubiquitin proteolytic pathway is responsible for the degradation of the bulk of cellular proteins including short-lived, regulatory, and misfolded/denatured proteins. Ubiquitin-mediated proteolysis involves covalent attachment of multiple ubiquitin molecules to the protein substrate and degradation of the targeted protein by the 26S proteasome. Recent understanding of the molecular mechanisms involved provides a framework to understand a wide variety of human pathophysiological states as well as therapeutic interventions. This review focuses on the response to hypoxia, inflammatory diseases, neurodegenerative diseases, and muscle-wasting disorders, as well as human papillomaviruses, cervical cancer and other malignancies.

Global and Site-Specific Quantitative Phosphoproteomics: Principles and Applications

Abstract: Protein phosphorylation is a key posttranslational modification, which reversibly regulates almost all processes in the living cell. Deregulated signaling is a hallmark of cancer and other diseases, and protein kinases are prominent drug targets. Phosphorylation events are commonly probed in a targeted manner by phosphorylation-specific antibodies. In contrast, advances in proteomics technology, including phosphopeptide enrichment, high-accuracy mass spectrometry, and associated bioinformatics now make it possible to analyze entire phosphoproteomes. Quantitative methods can assess the relative change in phosphorylation for several thousand sites in a single experiment. Here we review enrichment strategies and methods for mass spectrometric fragmentation and analysis of phosphopeptides. We also describe different quantitative methods and their application to problems in cell signaling and drug target discovery. Emerging phosphoproteomics technologies are becoming more comprehensive, robust, and generically applicable to a wide range of questions, including areas outside traditional eukaryotic cell signaling such as Ser/Thr/Tyr signaling in bacteria.

Epigenetics, DNA Methylation, and Chromatin Modifying Drugs

Abstract: Evidence is emerging that several diseases and behavioral pathologies result from defects in gene function. The best-studied example is cancer, but other diseases such as autoimmune disease, asthma, type 2 diabetes, metabolic disorders, and autism display aberrant gene expression. Gene function may be altered by either a change in the sequence of the DNA or a change in epigenetic programming of a gene in the absence of a sequence change. With epigenetic drugs, it is possible to reverse aberrant gene expression profiles associated with different disease states. Several epigenetic drugs targeting DNA methylation and histone deacetylation enzymes have been tested in clinical trials. Understanding the epigenetic machinery and the differential roles of its components in specific disease states is essential for developing targeted epigenetic therapy.

The Role of Gβγ Subunits in the Organization, Assembly, and Function of GPCR Signaling Complexes

Abstract: The role of Gβγ subunits in cellular signaling has become well established in the past 20 years. Not only do they regulate effectors once thought to be the sole targets of Gα subunits, but it has become clear that they also have a unique set of binding partners and regulate signaling pathways that are not always localized to the plasma membrane. However, this may be only the beginning of the story. Gβγ subunits interact with G protein–coupled receptors, Gα subunits, and several different effector molecules during assembly and trafficking of receptor-based signaling complexes and not simply in response to ligand stimulation at sites of receptor cellular activity. Gβγ assembly itself seems to be tightly regulated via the action of molecular chaperones and in turn may serve a similar role in the assembly of specific signaling complexes. We propose that specific Gβγ subunits have a broader role in controlling the architecture, assembly, and activity of cellular signaling pathways.

The TRPC Class of Ion Channels: A Critical Review of Their Roles in Slow, Sustained Increases in Intracellular Ca2+ Concentrations*

Abstract: The realization that there exists a multimembered family of cation channels with structural similarity to Drosophila's Trp channel emerged during the second half of the 1990s. In mammals, depending on the species, the TRP family counts 29 or 30 members which has been subdivided into 6 subfamilies on the basis of sequence similarity. TRP channels are nonselective monovalent cation channels, most of which also allow passage of Ca2+. Many members of each of these families, but not all, are involved in sensory signal transduction. The C-type (for canonical or classical) subfamily, differs from the other TRP subfamilies in that it fulfills two different types of function: membrane depolarization, resembling sensory transduction TRPs, and mediation of sustained increases in intracellular Ca2+. The mechanism(s) by which the C-class of TRP channels—the TRPCs—are activated is poorly understood and their role in mediating intracellular Ca2+ increases is being questioned. Both of these questions—mechanism of activat...

The COXIB Experience: A Look in the Rearview Mirror

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used prescription and nonprescription drugs in the world. The discovery of cyclooxygenase (COX) as the target of NSAIDs, the subsequent identification of two isoforms of COX (COX-1 and COX-2), and studies of their regulation and sites of expression led to the hypothesis that COX-2 is the molecular target for the anti-inflammatory and analgesic effects of NSAIDs. A corollary was that COX-2-selective inhibitors (COXIBs) would retain the desirable effects of NSAIDs without some of their liabilities (e.g., gastrointestinal toxicity, which was ascribed to COX-1 inhibition). The first marketed COXIBs exhibited reduced gastrointestinal side effects relative to traditional NSAIDs and were enormous commercial successes. However, clinical trials testing the hypothesis that COXIBs prevent recurrence of premalignant colon polyps uncovered adverse cardiovascular effects that are mechanism based. This review provides an overview of the discovery, development, and difficulties of the COXIBs, a perspective on what has been learned, and speculation on the way forward.

Sorting out astrocyte physiology from pharmacology.

Abstract: A number of exciting findings have been made in astrocytes during the past 15 years that have led many researchers to redefine how the brain works. Astrocytes are now widely regarded as cells that propagate Ca 2+ over long distances in response to stimulation, and, similar to neurons, release transmitters (called gliotransmitters) in a Ca 2+ -dependent manner to modulate a host of important brain functions. Although these discoveries have been very exciting, it is essential to place them in the proper context of the approaches used to obtain them to determine their relevance to brain physiology. This review revisits the key observations made in astrocytes that greatly impact how they are thought to regulate brain function, including the existence of widespread propagating intercellular Ca 2+ waves, data suggesting that astrocytes signal to neurons through Ca 2+ -dependent release of glutamate, and evidence for the presence of vesicular machinery for the regulated exocytosis of gliotransmitters.

Progress in Genetic Studies of Pain and Analgesia

Abstract: Interindividual variability in pain sensitivity and the response to analgesic manipulations remains a considerable clinical challenge as well as an area of intense scientific investigation. Techniques in this field have matured rapidly so that much relevant data have emerged only in the past few years. Our increasing understanding of the genetic mediation of these biological phenomena have nonetheless revealed their surprising complexity. This review provides a comprehensive picture and critical analysis of the field and its prospects.

Immunodrugs: Therapeutic VLP-Based Vaccines for Chronic Diseases

Abstract: Worldwide, the prevalence of noncommunicable chronic diseases is increasing. The use of vaccines to induce autoantibodies that neutralize disease-related proteins offers a means to effectively and affordably treat such diseases. Twenty vaccines designed to induce therapeutic autoantibodies were clinically tested in the past 12 years. Immunodrugs are therapeutic vaccines comprising virus-like particles (VLPs) covalently conjugated with self-antigens that induce neutralizing autoantibody responses. Four such VLP-based vaccines have been clinically tested and one has achieved proof of principle: a reduction of blood pressure in hypertensive patients. To facilitate preliminary clinical testing, novel nonclinical study programs have been developed. Safety study designs have considered the underlying B and T cell immunology and have examined potential toxicities of vaccine components and primary and secondary pharmacodynamic action of the vaccines.

Autonomic Neurotransmission: 60 Years Since Sir Henry Dale

Abstract: In the early twentieth century, Sir Henry Dale and others described brilliant studies of autonomic neurotransmission utilizing acetylcholine and noradrenaline. However, within the past 60 years, new discoveries have changed our understanding of the organization of the autonomic nervous system, including the structure and function of the nonsynaptic autonomic neuroeffector junction, the multiplicity of neurotransmitters, cotransmission, neuromodulation, dual control of vascular tone by perivascular nerves and endothelial cells, the molecular biology of receptors, and trophic signaling. Further, it is now recognized that an outstanding feature of autonomic neurotransmission is the inherent plasticity afforded by its structural and neurochemical organization and the interaction between expression of neural mediators and environmental factors. In this way, autonomic neurotransmission is matched to ongoing changes in demands and can sometimes be compensatory in pathophysiological situations.

Quantitative disease, drug, and trial models.

Abstract: Quantitative disease-drug-trial models allow learning from prior experience and summarize the knowledge in a ready to apply format. Employing these models to plan future development is proposed as a powerful solution to improve pharmaceutical R&D productivity. The disease and trial models are, to a large extent, independent of the product, but the drug model is not. The goals are to apply the disease and trial models to future development and regulatory decisions, and publicly share them. We propose working definitions of these models, describe the various subcomponents, provide examples, and discuss the challenges and potential solutions for developing such models. Building useful disease-drug-trial models is a challenging task and cannot be achieved by any single organization. It requires a consorted effort by industry, academic, and regulatory scientists. We also describe the strategic goals of the FDA Pharmacometrics group.

Lithium's Antisuicidal Efficacy: Elucidation of Neurobiological Targets Using Endophenotype Strategies

Abstract: Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and...

Emerging pharmacology: inhibitors of human immunodeficiency virus integration.

Abstract: The first integrase inhibitor licensed to treat HIV-1 infection was approved in late 2007, more than a decade after the introduction of the first inhibitors of the HIV-1 reverse transcriptase and protease. The unique biochemical and molecular mechanism of action of this novel class of antiretroviral drugs is the fundamental basis for their activity in treating multidrug-resistant HIV-1 infection and is important for understanding both the cellular and in vivo pharmacology and metabolism of these agents. In addition, available pharmacokinetic and drug interaction data for raltegravir and elvitegravir, the two integrase inhibitors that are the most advanced in clinical development to date, are reviewed.

Topical Microbicides to Prevent HIV: Clinical Drug Development Challenges

Abstract: Microbicides, substances applied topically to prevent sexual HIV infection, are needed to empower receptive sexual partners with effective prevention methods. Several large microbicide trials, however, failed to demonstrate efficacy, thus motivating a reevaluation of the current microbicide development paradigm, which has been largely empirically based. Microbicide use occurs in a highly complex environment involving multi-level interactions, behavioral and biochemical, among host, virus, and drug, yet many details of these interactions remain unknown. Fundamental information regarding virus and drug distribution over time in sexually receptive body compartments that is necessary to design a microbicide able to outdistance and outlast the virus is largely absent. Recent efforts have been made to establish a simple conceptual framework for obtaining the knowledge that is likely to inform a more mechanistic, model-based development paradigm. These efforts have also advanced the development of numerous methodological approaches to obtain the knowledge needed to improve microbicide development.

Mycobacterial Subversion of Chemotherapeutic Reagents and Host Defense Tactics: Challenges in Tuberculosis Drug Development

Abstract: Recent worldwide emergence of multidrug-resistant and extensively drug-resistant tuberculosis is threatening to destabilize tuberculosis control programs and urging global attention to the development of alternative tuberculosis therapies. Major roadblocks limiting the development and effectiveness of new drugs to combat tuberculosis are the profound innate resistance of Mycobacterium tuberculosis to host defense mechanisms as well as its intrinsic tolerance to chemotherapeutic reagents. The triangle of interactions among the pathogen, the host responses, and the drugs used to cure the disease are critical for the outcome of tuberculosis. We must better understand this three-way interaction in order to develop drugs that are able to kill the bacillus in the most effective way and minimize the emergence of drug resistance. Here we review our recent understanding of the molecular basis underlying intrinsic antibiotic resistance and survival tactics of M. tuberculosis. This knowledge may help to reveal current targets for the development of novel antituberculosis drugs.