Welcome to Molecular Pharmacology! PHRMSCI 170ATop 5 RulesDefinitionsSlide 4Slide 5Slide 6DefinitionsDrug NomenclatureExample: TylenolPotency and EfficacyChapter 1: Receptors and Concentration-Response RelationshipsSites of Drug ActionReceptorsReceptors: Lock and Key HypothesisMolecular flexibility & Our Evolving Ideas of Molecular RecognitionAgonists and AntagonistsSlide 17PowerPoint PresentationFeatures of ReceptorsSlide 20Ligand-receptor InteractionsSlide 22Receptor SuperfamiliesSlide 24Ligand-gated Ion ChannelsLigand-gated ion channelsSelected Drugs Acting on Ion ChannelsG-Protein-Coupled ReceptorsSlide 29Selected Drugs Acting on G-Protein-Coupled ReceptorsReceptor Tyrosine KinasesSlide 32Slide 33Selected Drugs Acting on Receptor Tyrosine KinasesNuclear Hormone ReceptorsSlide 36Selected Drugs Acting on Nuclear Hormone ReceptorsOther Drug TargetsConcentration-response RelationshipDrug ResponsesSlide 41Slide 42Slide 43Law of Mass ActionAntagonistsAntagonists and AgonistsSlide 47Slide 48Slide 49Signal Amplification: Spare ReceptorsSlide 51Receptor Desensitization and SupersensitivityReceptor DesensitizationSlide 54Slide 55Receptor Supersensitivity Up-regulationSlide 57Welcome toMolecular Pharmacology! PHRMSCI 170ATop 5 Rules 5) Attend the lectures and discussions4) Pay attention in the classroom (or to the screen) and don’t daydream or sleep or FB or text unless you have to!3) Read the chapter prior to coming to the class (You need to have the textbook!)2) Don’t memorize…Understand!1) Learn for life!Definitions•PharmacologyThe study of drugs in its broadest sense•Drugs?Specific molecules: small molecules and big molecules InsulinCaffeineDefinitions•PharmacodynamicsWhat the drug does to the body. The molecular mechanism of action of drugsDefinitions•PharmacokineticsWhat the body does to the drug.Concentration, metabolism, eliminationDefinitions•PharmacogenomicsGenetic differences resulting in different responsesDefinitions •ToxicologyStudy of poisonsSigns and symptoms of toxicityDrug Nomenclature•Chemical Name•Generic Name or Nonproprietary•Brand/Trade Name or ProprietaryExample: Tylenol•Chemical NameN-acetyl-p-aminophenol •Generic Name or Nonproprietary Name Acetaminophen•Brand/Trade Name or Proprietary NameTylenol (USA)Abenol (CANADA) Acamol (CHILE) Acetamol (ITALY) Afebrin (HONG-KONG) Algiafin (CHILE) Alvedon (SWEDEN) Apirex (FRANCE) Arfen (AFRICA)Potency and Efficacy•Potency refers to the amount of drug necessary to elicit a response •Efficacy, or effectiveness, of a drug is its ability to produce the maximal desired responseChapter 1:Receptors and Concentration-Response RelationshipsSites of Drug Action•ReceptorsMembrane Proteins•EnzymesCytoplasmic enzyme Extracellular enzyme• Nucleic AcidReceptors•Generalized Receptors: Molecules, such as enzymes and DNA, which are essential to a cell's normal biological function or replication•Specialized Receptors: Biological molecules that have evolved specifically for intercellular communicationReceptors:Lock and Key HypothesisMolecular flexibility & Our Evolving Ideas of Molecular RecognitionRigid “lock-and-key” (~1900)Induced fit (~ 1958)Conformational ensembles (~ 2000)Receptor (aka protein)LigandReceptor exists in a population of energetically low-lying sub-states, or “conformational ensemble”Ligand binds to one of these sub-states and shifts the population toward the favorable bound conformationEAgonists and Antagonists•Agonists Bind to the receptor and activate it •AntagonistsBind to the receptor but do not have the unique structural features necessary to activate itInhibit activation by agonistsAgonists and Antagonistshttp://www.neurosurgical.com/neuro_medical_info/medicines/Figure 1-2. Major features of receptors. These include embedding in a membrane, glycosylated chains on the extracellular side, binding sites on the extracellular side for an endogenous transmitter (dark blue symbols) with two molecules sometimes needing to be bound (as shown here) to activate the transmembrane receptor. Drugs can use many sites on the receptor: (1) The agonist and antagonist compete with the endogenous transmitter for binding sites; (2) allosteric agonists or antagonists enhance or block the signal, respectively, by binding to allosteric sites that influence (wavy line) signal transmission; and (3) other drugs can block signal transmission within the membrane or at intracellular signal reception points.Downloaded from: StudentConsult (on 20 July 2005 11:01 PM)© 2005 Elsevier Major Features of ReceptorsFeatures of Receptors•Protein: Lipoprotein, glycoprotein with one or more subunits. •Different tissue distributions. •Drug binding is usually reversible and stereoselective. •Specificity of binding not absolute, leading to nonspecific effects. •Receptors are saturable because of their finite number.Features of Receptors•Agonist activation results in signal transduction. •Signal can be amplified by intracellular mechanisms. •Drugs can enhance, diminish, or block signal generation or transmission. •Can be up-regulated or dow-nregulated.Ligand-receptor InteractionsDrug+Receptor DR DR*RESPONSEFigure 1-1. Types of chemical bonds and attractive forces between molecules that are pertinent to the interaction of drugs with their active sites.Downloaded from: StudentConsult (on 20 July 2005 11:01 PM)© 2005 Elsevier Drug Binding to ReceptorsReceptor Superfamilies1. Ligand-gated ion channels2. G-protein-coupled receptors3. Receptor tyrosine kinases4. Nuclear hormone receptorsReceptor Superfamilieshttp://pharmacologycorner.com/video-animation-mechanism-of-ionotropic-receptors-or-ligand-gated-ion-channels-lgics/Ligand-gated Ion Channels •Found in brain, peripheral nervous system, heart, and the neuromuscular junction •Responsible for FAST synaptic transmission•Receptor is an ion channel •Ligand binds to & opens channel •Example: Neurotransmitter-gated ion channels •Acetylcholine (Ach) binds to receptor and opens Na+/K+ channelsLigand-gated ion channelshttp://pharmacologycorner.com/video-animation-mechanism-of-ionotropic-receptors-or-ligand-gated-ion-channels-lgics/Selected Drugs Acting on Ion Channels •Lidocaine (Xylocaine)Na+ channel blocker. Antiarrhythmics•Amlodipine (Norvasc)Ca2+ channel blocker. Anti-hypertensive •Gabapentin (Neurontin) GABA receptors. Anti-epilepticG-Protein-Coupled Receptors •The most important class of receptors