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  • Ion Channels: 3 Modules

    Contains 3 Component(s) Recorded On: 10/06/2011

    3 Modules

    Module 1: Ion Channels: Basic Principles and their Application to Assay Design

    Module 2: Impact of Technology Evolution on Ion Channel Drug Discovery

    Module 3: Ion Channel Physiology and Drug Discovery


    Claire Townsend

    Manager

    Dr. Claire Townsend is Manager of the Cellular Targets and Electrophysiology group at GlaxoSmithkline in Research Triangle Park, North Carolina. She has over 12 years of experience in the field of ion channel drug discovery.

    Ronald Knox

    Group Leader

    Dr. Ronald Knox is currently a Group Leader of Lead Evaluation & Ion Channel Technologies at Bristol-Myers Squibb (BMS) at their Wallingford site in Connecticut, USA. These groups are responsible for all of the high throughput in vitro lead optimization SAR assays for Neuroscience & Virology for BMS. Prior to joining BMS, he conducted post doctoral studies in the area of ion channel modulation at Yale University. Dr. Knox obtained his Bachelor of Science degree in Pharmacology at Glasgow University, Scotland and his Ph.D, studying opioid receptor regulation of nociceptive spinal neurotransmission at University College London, England.

    Peter Miu

    Research Scientist

    Dr. Peter Miu spent 14 plus years as a research scientist for pharmaceutical companies in both Canada and US, specializing in biophysical and pharmacological characterization of ion channels and membrane transporters using conventional and automated patch-clamp platforms.

    This module will introduce the fundamental properties of ion channels: their structure, biophysical characteristics, and how ion channel function may be altered by natural products and drugs. Several examples illustrating how this knowledge can be applied to the design of ion channel assays will be presented.

    This module will examine the research and development story of major classes of marketed ion channel drugs in the context of the critical technologies which enabled their discovery. Two examples which figure prominently in both modern cardiovascular medicine, and in the development of technology strategies for prosecuting ion channel targets broadly, are the quinidine class of Na+-channel blockers, and the dihydropyridine class of Ca++-channel blockers.

    Na+ channel activity in myocytes under such conditions demonstrated a much higher open probability relative to their Na+ channel counterparts in the myocytes of regions unaffected by hypoxia. Further studies revealed what we know now, that clinically utilized Na+ channel blocking agents bind with much higher affinity to Na+ channels in their open state relative to the closed state, and therein lies the explanation of why these drugs can be used clinically inhibit focal cardiac arrhythmias, while sparing the excitability and contractility of myocytes in healthy regions of the heart.

    Dihydropyridine L-type Ca2+ channels found in peripheral arterial smooth muscle cells due to their inherent depolarized resting membrane potential. On the other hand, L-type Ca2+ channels expressed in the heart cardiomyocytes spend most of their time in a non-inactivated conformational state, which does not bind dihydropyridine drugs with high affinity, and therein lies the clinically relevant therapeutic index of this class of ion channel modulator drugs.

    Both of these examples underscore the point that "functional selectivity" of ion channel modulator drugs is not only possible, but is of enormous importance for the discovery & clinical development of future ion channel drugs. Secondly, these classical examples illustrate beautifully why it is critical to develop ion channel assays that allow full voltage & time dependent control over ion channel function in assay screening tiers. Without this ability, it is impossible to classify compounds by their relative rate or state dependence, and thus impossible to leverage functional selectivity to create safer drugs. A critical technology which provides discrete, micro-second scale command of membrane voltage in intact cells is patch clamp electrophysiology, and it is why this technology is critical to the characterization of ion channel drugs. A large technology landscape has grown around the core patch-clamp technique over the last 3 decades as drug discovery pursues new ion channel targets and novel mechanisms of action. In module 2 we will further explore the ion channel technology landscape, and how it has impacted the discovery of next generation ion channel drugs.

    This course will focus on the history of ion channels in research and introduce various roles of ion channels in both excitable and non-excitable cells. Examples of target and lead validation will be discussed to give an overall understanding of the strategy and methods now practiced in a drug discovery environment.

    Ion channels are pore-forming transmembrane proteins that play critical roles in cell-to-cell communication and signal transduction in excitable and non-excitable cells. Ion channels can be divided into two broad classes: voltage- and ligand-gated. Voltage-gated ion channels respond to changes in the transmembrane potential, whereas ligand-gated ion channels respond to the binding of an endogenous ligand to its binding site. When ion channels are activated, ions such as sodium, calcium, potassium and chloride flow through the open channel pores down their electrochemical gradients.

    The importance of ions in myocytes and neurons was first demonstrated in the late 1800's when Ringer showed that an isolated frog heart would stop beating spontaneously if sodium, calcium, and potassium salts were omitted from the water bathing the heart, leading to the conclusion that ions were essential in sustaining spontaneous muscle contraction. Later using silver wire electrodes, intracellular recordings from squid giant axons provided the critical evidence that ionic currents are involved in the generation of action potential. These studies demonstrated that sodium and potassium concentration gradients between inside and outside the neuron are vital in maintaining physiological resting membrane potential and in generating action potentials. Decades long studies showed that changes in membrane potential mediated by both voltage- and ligand-gated ion channels play a critical role in physiological processes such as nociception and cognition in excitable cells.

    Development of patch clamp recording techniques in the 1970's expanded the study of ion channels in both excitable and non-excitable cells such as lymphocytes, renal and epithelial cells. Patch clamp technology along with molecular biology identified numerous mutations in channel physiology underlying many diseases. For example, upregulation of protein expression or point mutation of a single amino acid in the peptide sequence could alter ion channel function. These studies provided insights into the mechanisms of channel function in normal and diseased state, thus exposing ion channel targets for therapeutic intervention.

    In an industry setting, knowledge obtained from basic research is applied toward drug development. The critical stages of an early drug discovery process include high-throughput screening, hit confirmation, lead identification and finally, lead optimization. The ultimate goal of any drug development program involving ion channel targets is to identify a potent and highly selective molecule that can rectify ion channel dysfunction.

  • Current and Emerging Technologies and Applications for ADMET: Novel Aspects of Risk Assessment: 4 Modules

    Contains 4 Component(s) Recorded On: 05/26/2011

    4 Modules

    Module 1: MEMs Devices as Animal Alternatives for Tox, Drug Metabolism and Sensitization Assessment

    Module 2: New ADME-Tox Technologies: In Silico Approaches to Predictive ADME-Tox Evaluation

    Module 3: In Vitro Models for the Study of Drug Transporters

    Module 4: Application of Pharmacogenetics to Predictive ADMET

    Tim Maguire

    Associate Research Professor

    Dr. Tim Maguire received a B.S. in Chemical Engineering from Rutgers University. His Ph.D., also from Rutgers and under the advisement of professor Martin Yarmush, was in the field Biomedical Engineering and focused on applying novel polymer systems with embryonic stem cells to generate controlled differentiation systems. Tim also completed an NIH-sponsored training program, the Biotechnology Training Program, and an NSF sponsored IGERT on microscale interfaces. Following the completion of his Ph.D., Tim went on to work in a formulation group at Merck for 2 years, were he helped to implement new solid dispersion technologies, as well as establish a computational fluid dynamic program. He then moved to a startup company where he was involved in the creation of in vitro drug screening systems, integrating optimized human hepatocyte cultures with microfluidic systems.

    He is currently an Associate Research Professor at Rutgers University, focusing on translation of biomedical research. Collectively, Tim's work throughout his career has focused on implementing novel technologies and in silico approaches within the pharmaceutical and biotech industries. Through this work Tim has generated over 20 publications, over 40 presentations, and 3 patents.

    Eric Novik

    Research

    Dr. Eric Novik received a B.S. in Biomedical Engineering from Rutgers University. His Ph.D., also from Rutgers and under the advisement of Professor Martin Yarmush, was in the field Biomedical Engineering and focused on characterization and optimization of platforms for embryonic stem cell differentiation into liver lineage cells. Eric has been at a small biotechnology company, for 4 years and is involved in all aspects of development and commercialization of patented microfluidic, cell-based platforms for use in drug discovery and development, consumer and industrial product testing and related fields.

    Throughout his experience, he has generated over 15 publications, 30 presentations, and 3 patents, and has gained a great appreciation for the establishment of alternative technologies to animal testing. It is Eric's hope that one day we will have screening modalities capable of replacing animal testing, and with the potential to provide even greater human relevant data then is capable with current animal systems.

    Simon Thomas

    Head of Scientific Computing

    Simon Thomas is the head of Scientific Computing at Cyprotex Discovery Ltd, where he is responsible for the development of predictive models for ADME properties, in vivo pharmacokinetics and toxicity. He has more than 20 years experience of working in the area of biochemical, physiological and pharmacological modelling and simulation.

    Chris Bode

    VP Corporate Development

    Dr. Bode is a pharmacologist with a background in drug discovery at Sterling Winthrop and Rhone-Poulenc Rorer and eight years in the human hepatocyte business prior to the past five years with Absorption Systems.

    Wolfgang Sadee

    Professor

    Wolfgang Sadee is the Felts Mercer Professor of Medicine and Pharmacology, and Director of the OSU Program in Pharmacogenomics. He also serves as Principal Investigator of the XGEN Program at OSU, part of the NIH Pharmacogenomics Research Network.

    This presentation will describe ongoing research and development projects, the aim of which is to construct in vitro alternatives for animal testing in three industrial relevant research sectors:

    1. drug metabolism;
    2. toxicology assessment;
    3. delayed type contact hypersensitivity.

    Each of these in vitro surrogates could be used for the screening of new chemical compounds and formulations. For the areas of drug metabolism and toxicology assessment we will describe devices that focus on the integration of optimized hepatocyte configurations in conjunction with the application of flow. For the hypersensitivity assay we will describe a microdevice that contains several communicating compartments which model the skin, a migrating dendritic cell population, and nearby lymph node.

    In each of the systems we will provide an overview of the history, challenges, and progress, and will give an in depth analysis of the results that can be obtained from such devices. Future applications of the approach will also be discussed.

    In determining theADME-Tox properties of novel compounds - whether pharmaceuticals, neutraceuticals, cosmetics ingredients, chemicals or others - use of in silico approaches can serve several valuable purposes:

    • Replacement of in vitro with in silico approaches can reduce costs or, alternatively, enable screening of larger numbers of compounds than is feasible with in vitro methods.
    • Integrative approaches, such as physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PBPK/PD) modelling, can be used to combine data on multiple properties, in order to predict compounds' behaviour in vivo, thus reducing the need for in vivo experimentation in animals or humans.
    • Sensitivity and error analyses of model output can be used to prioritise properties and compounds for further investigation, permitting maximum return on investment.

    This module will describe and illustrate application of in silico methods these approaches in determining the ADME-Tox properties of pharmaceuticals and other compounds.

    Drug regulatory agencies in major markets throughout the world now require in vitro data on interactions of NCEs with drug transporters, mainly with regard to predicting clinical drug-drug interactions. Various in vitro models are used in this effort, each with its own advantages and disadvantages. The lack of specific pharmacologic reagents (probe substrates and inhibitors) for most transporters puts a premium on the need for definitive model systems.

    This course will provide a survey of currently available in vitro (cell-based and subcellular) assay formats for drug transporters, including some recently developed, novel technologies.

    A critical goal of drug discovery and development is the design of compounds that have suitable pharmacokinetic properties and the ability to reach the target tissue and molecular target site. Hundreds of genes are involved in encoding drug metabolizing enzymes and membrane transporters.

    Large interindividual differences in ADMET parameters are detrimental to successful drug therapy as some subjects may suffer adverse drug effects while others may not experience the desired effects. Depending upon the drug substance, a portion of the variability is caused by genetic variants in key genes involved in ADMET processes. In particular, polymorphic cytochrome P450 enzymes play a prominent role, while increasing evidence also points to membrane transporters.

    The seminar will address the question under which circumstances genetic variants are important in drug discovery and development. As genomic data have become routine additions to New Drug Applications, one needs to understand how this approach facilitates the path to FDA NDA approval and potentially optimizes individual drug therapy.

  • Introduction to Biomarkers and Their Utilization in Pharmaceutical Science: 4 Modules

    Contains 4 Component(s) Recorded On: 09/30/2010

    4 modules

    Module 1: Biomarkers: Old, New, Improved and Approved

    Module 2: Discovery, Development and Utilization of Protein Biomarkers to Improve Pharmaceutical Decision-Making and Increase Return on R&D Investments

    Module 3: Utilizing SNPs to Identify High-Risk Men for Prostate Cancer Screening and Chemoprevention

    Module 4: Quantitative Imaging Systems in Drug-Discovery Research: A Picture May Be Worth a ThousandBiomarkers

    William Mattes

    Founder & Principal

    William B. Mattes, PhD, DABT, is the founder and principal of PharmPoint Consulting, providing expertise in drug development, biomarker implementation, mechanistic, genetic, molecular and genomic toxicology, and collaboration leadership.

    Dr. Mattes' background is in drug development, genetic toxicology, molecular toxicology, mechanistic toxicology, and toxicogenomics, spanning more than 25 years. Prior to establishing PharmPoint Consulting, Dr. Mattes was Director of Toxicology at the Critical Path Institute, where he developed and directed the Predictive Safety Testing Consortium (PSTC), a collaboration of 16 of the world's major pharmaceutical companies, with FDA and EMEA advisors, with the goal of qualifying new biomarkers for drug safety in a regulatory setting. Dr. Mattes was also senior scientific director of toxicogenomics at Gene Logic; associate director of toxicogenomics at Pharmacia Corp; group leader of experimental toxicology at Ciba Pharmaceuticals; and group leader of molecular and cellular toxicology, Ciba-Geigy Agricultural Chemical Division.

    Dr. Mattes received his BA from the University of Pennsylvania and Ph.D. in biological chemistry from the University of Michigan, Ann Arbor. He did his postdoctoral training in biochemistry at the Johns Hopkins University, and was a staff fellow at the National Cancer Institute. In 1997, Dr. Mattes became a diplomat of the American Board of Toxicology. He is a full member of the Society of Toxicology. As part of his involvement with the International Life Sciences Institutes Health and Environmental Sciences Committee on the application of genomics to risk assessment, Dr. Mattes chaired the subcommittee that established a public toxicogenomics database at the European Bioinformatics Institute. His research interests include bioinformatics, cross-species comparisons of molecular responses, mitochondrial toxicity and dose/time/response relationships in gene expression. He also currently fills the guitar chair for the group Jazzicology at the American College of Toxicology annual meeting.

    Kevin Duffin

    Senior Research Fellow

    Dr. Kevin Duffin received his B.S. degree in chemistry from the University of Wisconsin-Madison and his Ph.D. degree in analytical chemistry from Indiana University. After postdoctoral work in the Department of Veterinary Medicine at Cornell University, he joined Monsanto/Searle in St. Louis, Missouri (later to become Pharmacia and then Pfizer through a series of mergers/acquisitions).

    Some of Dr. Duffin's technical accomplishments include: establishment of electrospray mass spectrometry when it was a novel technology; implementation of cassette-dosing PK in discovery research for high-throughput half-life and oral bioavailability data; establishment of proteomics and imaging programs for biomarker discovery; and integration of biomarker strategies across discovery and clinical groups. He worked on numerous discovery projects that led to commercial products, including Celebrex, Bextra, Posilac, and Vistive soybeans. At the time he left Monsanto/Searle/Pharmacia, Dr. Duffin led the company's biomarker discovery program and served as Director of Analytical Sciences.

    Dr. Duffin joined Eli Lilly and company in 2003 and currently holds the title of Senior Research Fellow. At Lilly, his leadership responsibilities have included oversight of: biomarker strategy across Lilly's portfolio; biomarker discovery and development implementation within project phase; and leadership of proteomics, assay development, receptor occupancy, and preclinical imaging groups. He currently serves as a member of the Discovery Executive Team and the target development portfolio committee, and oversees Six Sigma efforts to improve LRL Discovery productivity. Dr. Duffin also leads a laboratory that is applied to novel target and biomarker identification/validation in osteoarthritis, neurodegeneration, and chronic kidney disease areas. Dr. Duffin is the author of 47 publications and several granted/submitted patents. He was awarded the Lilly Research Laboratories President's Award in 2004 for his development of cohesive biomarker strategies to support Lilly's project and program phase portfolio.

    Jianfeng Xu

    Professor

    Dr. Jianfeng Xu is a professor of Genomic and Personalized Medicine, Cancer Biology, & Urology at Wake Forest University School of Medicine. He serves as Director for the Center for Cancer Genomics. Dr. Xu was trained in medicine, epidemiology, and human genetics. He is a leading genetic epidemiologist in prostate cancer research and has published over 170 peer- reviewed papers in this area, in the New England Journal of Medicine, Science, Nature Genetics, and other journals.

    Dr. Xu has contributed significantly to the discovery of highly penetrant prostate cancer susceptibility genes using positional cloning methods and low penetrant SNPs in genome-wide association studies. His recent efforts focus on risk prediction using genetic markers & family history.

    Bruce Gitter

    Senior Principal Scientist

    Dr. Bruce D. Gitter joined Covance Laboratories as a senior principal scientist and manager in October, 2008 in the newly formed Department of Molecular and Anatomical Imaging in Covance Laboratories. He leads an in vivo and ex vivo nuclear medicine imaging group focusing on pre-clinical neuroscience, cardiovascular, diabetes, and cancer models. In addition, his team provides image validation of in vivo imaging models using standard and specialized histological methods. A key area of interest for Dr. Gitter's team is the use of small animal PET imaging and ex vivo autoradiography to examine neurodegenerative changes in rodent disease models and pharmacodynamic effects of psychiatric drugs on local cerebral glucose utilization in the rodent CNS. His group also utilizes in vitro receptor autoradiography and immunohistochemistry to discover and validate novel tracer biomarkers for multiple therapeutic applications.

    Dr. Gitter joined Eli Lilly and Company as a research scientist in 1983 in biochemical pharmacology research where he developed novel high-throughput drug discovery screens for immunomodulatory agents. While in neuroscience research (1992-2004), Dr. Gitter made significant scientific and leadership contributions to the discovery and early phase clinical development of neurokinin-1 receptor antagonists and two current investigational Alzheimer's disease drugs. Upon joining Integrative Biology in 2004, he established and led an imaging biomarker discovery and validation laboratory supporting drug discovery, toxicology, and development teams, with a focus on nuclear medicine-based imaging. In addition, he provided leadership in the utilization of the FIPNET model through external partnerships with multiple institutions.

    Dr. Gitter received a Bachelor of Science degree in biochemistry and chemistry from the University of Georgia in 1975. He was awarded a Master of Science degree in microbiology in 1976, and Doctor of Philosophy degree in zoology (immunoparasitology) in 1981, also from the University of Georgia. Dr. Gitter completed a postdoctoral fellowship in immunology at Duke University Medical Center from 1981-1983. He is currently adjunct professor of radiology, Indiana University School of Medicine, a member of the Society for Neuroscience, the Alzheimer's Association, the International Society for NeuroImmunomodulation, and the scientific advisory board for the Indiana Neuroimaging Symposium. In addition, Dr. Gitter serves as an ad hoc reviewer for multiple scientific journals.

    Jeffrey Wolos

    Head of Department of Molecular and Anatomical Imaging

    Dr. Jeffrey A. Wolos is the acting head of the Department of Molecular and Anatomical Imaging at Covance Laboratories. The Imaging Group is composed of two sections, Molecular and Anatomical Imaging (which Dr. Wolos also leads) and Nuclear Medicine. Scientists in the Molecular and Anatomical Section use MR, CT, optical, ultrasound, thermal, and laser Doppler imaging to investigate mechanism of action, determine the efficacy of potential drugs in multiple therapeutic areas, and to evaluate the safety/toxicity of compounds under consideration.

    Dr. Wolos joined Marion Merrell Dow Research Institute in 1986 as a research scientist in the Department of Immunology and Inflammation. He remained with the company for 16 years, advancing to Section Head of the Rheumatology Disease Group in what had become Aventis Pharmaceuticals. His research and drug discovery contributions focused on modulation of the immune response and inhibition of inflammation, specifically in autoimmune disease and allergy/asthma. In 2002 Dr. Wolos was recruited to Eli Lilly and Company to help restart their Inflammation Research Group. At Lilly he served in a number of scientific and administrative positions, the most senior of which was head of Rheumatoid Arthritis/Asthma In Vivo Pharmacology in the Bone and Inflammation Disease Group. In 2004 Dr. Wolos moved to the Department of Integrative Biology, developing preclinical and translational biomarker strategies (protein and imaging) for diseases of interest to the therapeutic areas.

    In 2008 Dr. Wolos joined Covance Laboratories, where as head of Imaging he leads a group containing both expert imaging scientists and biologists who have lead drug discovery projects in multiple therapeutic areas.

    Dr. Wolos received a Bachelor of Science degree in anatomy and physiology from Cornell University in 1972. After spending two years performing research in cardiovascular disease at Cornell Medical School in New York, he initiated graduate studies at Upstate Medical Center, S.U.N.Y., where he was awarded a Doctor of Philosophy degree in immunology/microbiology in 1979.

    Following a post-doctoral fellowship at the Fox Chase Cancer Center, Dr. Wolos began his independent research career as an assistant professor in the Division of Rheumatology at the Thomas Jefferson Medical College, where he investigated the cellular immunology of autoimmune disease.

    With the attention given over the last several years to biomarkers in drug development and clinical therapy, the attributes of more conventional biomarkers are often overlooked for their value as historical benchmarks. Clinical chemistry, hematology, and urinalysis provide informative examples, and with these as a background this module will examine the various types, applications, and limitations of biomarkers with an eye toward their role in drug development.

    Characteristics of predictive, diagnostic, prognostic, safety, pharmacodynamic, and exposure biomarkers will be discussed and the concept of biomarker qualification will be distinguished from that of validation. Finally, the role of formal regulatory review of qualification will be considered. This module should provide a basis for examining biomarker discovery and development in depth.

    Protein biomarkers are widely utilized for decision-making in preclinical research and clinical application. Well-known biomarkers, including LDL-cholesterol, Hb-A1C, and Her-2-Neu, are widely used in clinical practice for patient selection and determination of patient response to drug therapy. Continued improvement in health outcomes requires continued innovation in novel biomarker discovery, development, and application.

    This module will focus on strategy, approach, and cost of protein biomarkers relative to decisions enabled with their use. Examples of novel biomarker assays based on ELISA, mass spectrometry, and receptor occupancy will be used to demonstrate approaches to discovery, assay development, validation, and qualification of protein biomarkers.

    The lecture will discuss:

      1. Achievement in the discovery of risk-associated SNPs of prostate cancer;
      2. Development of a SNP panel for estimating absolute risk of prostate cancer;
      3. Performance of the SNP panel in identifying men at high risk for prostate cancer;
      4. Evaluation of clinical utility of the SNP panel in prostate cancer screening and chemoprevention; and
      5. Clinical and public health implications of this genomic approach.

    Biochemical and molecular biomarkers have revolutionized medicine and drug development, giving clinicians and researchers the ability to infer the biological status of patients and the response to drug interventions. Imaging biomarkers take that one step further. An imaging biomarker can be defined as an anatomic, functional, biochemical, or molecular parameter detectable with imaging methods. These methods can show the presence or progress of disease, the effectiveness or toxicity of investigative molecules or candidate drugs, and the response to therapy at the cellular and molecular level.

    Our presentation will describe how quantitative imaging systems, such as bioluminescence and near infrared imaging are used in pre-clinical drug discovery; and how other imaging systems such as laser doppler imaging (LDI), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and ultrasound serve as valuable tools both in pre-clinical drug discovery and the identification of clinically translatable biomarkers. We will also discuss how these imaging biomarkers are used to enhance and enable modern medicine.

  • Pharmacodynamics for Drug Discovery: 3 Modules

    Contains 3 Component(s) Recorded On: 03/03/2010

    3 modules

    Module 1: Basic Pharmacological Principles, Agonism and the Operational Model

    Module 2: Orthosteric and Allosteric Antagonism: Methods of Measurement

    Module 3: Structure of Drug Discovery Programs: Target Selection, Assay Development and Criteria for Activity


    Terry Kenakin

    Senior Research Pharmacologist

    Terry Kenakin obtained his B.S. in chemistry and Ph.D. in pharmacology at the University of Alberta, Canada. After three years at University College, London, UK he joined Burroughs-Wellcome as a Senior Research Pharmacologist. He then went on to join Glaxo, which became Glaxo-Wellcome and subsequently GlaxoSmithKline, where he is interested in the use of quantitative receptor pharmacology and theory to advance new drug-discovery programs within GlaxoSmithKline Molecular Discovery Research. He has written eight books on pharmacology and is co-Editor-in-Chief of the International Journal of Receptors and Signal Transduction and also Current Opinion in Pharmacology. His current interests center on the therapeutic exploitation of 7TM receptor functional selectivity and allosteric control of 7TM receptor signaling.

    In this webinar, the unifying ideas of affinity (derived from the Langmuir adsorption isotherm) and efficacy (as defined by Stephenson and then by Black and Leff) will be presented as well as their relationship to the behavioral system of nomenclature of full, partial and inverse agonist.

    The lecture will include a discussion of the common currency of pharmacology, dose-response curves (how to fit and interpret them), and the derivation and use of the Black/Leff Operational model for agonism, the standard model used to quantify and predict agonist effect in all systems. A short discussion on the optimal types of assays for screening vs. lead optimization for agonists also will be given.

    This lecture continues the series, changing gears from agonism to antagonism. The presentation is divided into two sections. The first is devoted to the biochemical mechanism of action of antagonists (orthosteric and allosteric- how to identify these antagonist types), and the uniquely different properties of orthosteric and allosteric ligands.

    The second section is devoted to how to apply the correct model(s) to measure the equilibrium dissociation constants of antagonists in pharmacological systems. Specifically, the concept of data-driven analysis of drug antagonism will be used as a means to identify and quantify antagonist activity. The lecture will end with a discussion of drug-discovery programs and logical strategies to pursue agonists and antagonists as therapeutic entities.

    This lecture completes the series, with a discussion of the use of pharmacology in practical drug discovery. Drug-discovery programs will be discussed in terms of identification of chemical and biological targets, the development of pharmacologic assays and the determination of active biological effect. The pharmacodynamic-pharmacokinetic interface also will be discussed in terms of possible sources of dissimulation between activity seen in vitro and in vivo.