Pharm Drug Receptor Dynamics PDF

PHARM DRUG RECEPTOR DYNAMICS Quick Review: 1.What is a Ligand? Signaling molecule 2.What is a Receptor? Biological target 3. What is an important factor in the ligand-receptor binding? -Shape and good size. Want between 100-1000 and fit the shape of the ligand and receptor when they are binding...

PHARM DRUG RECEPTOR DYNAMICS Quick Review: 1.What is a Ligand? Signaling molecule 2.What is a Receptor? Biological target 3. What is an important factor in the ligand-receptor binding? -Shape and good size. Want between 100-1000 and fit the shape of the ligand and receptor when they are binding. 4. What is an agonist? -Ligand binds and activates receptor 5. What is an antagonist? -Ligand binds but does not activate. Also, prevents an agonist from binding. 6. Describe pharmacodynamics in 3 words. -Drugs on the body. Pharmacodynamics (drugs on the body) -Most drugs bind to the cellular receptors -Initiate series of biochemical reactions after cell’s physiology. Drug receptors -Proteins or glycoproteins -Location: cell surface(most common). Organelle within the cell (nucleus). Cytoplasm. -There is a limited number of receptors in a cell. Receptor states - Can be active or inactive -Most are inactive -Depend on the ligand for effect -Those that are active, are active regardless of an agonist -Produce a physiological effect. Have a constitutive activity meaning they are always working. -Receptors exist in a reversible equilibrium. -IF inactive receptor turned on, eventually must turn off (If inactive turned on, eventually must be turned off. -IF active turned off, eventually must turn back on (If active is off, needs to be put back on) Receptor characteristics -Receptors are specific for their effect -Selective for their ligand (specific to shape, and fit) -Cellular response is proportional to the number of activated receptors -Factors affecting number of activated receptors (Concentration of drug. Affinity of drug for receptor) Activated receptors -Biologic effect of a drug is related to fraction of activated receptors -Response to a drug eventually plateus (reaches it’s max effect) -Critical proportion of receptors that must be bound for max effect. -Anywhere from 1-100% Depends on drug. Factors affecting activation of receptors -Plasma concentration of the drug. More ligands and more receptors occupied with ligand. More physiological response. -Affinity for the receptor (Greater affinity, longer ligand will stay bound to the receptor). Greater attraction, the longer they will stay bonded. How is this measured? Concentration of drug that occupies 50% of available receptors. This then is associated with a low dissociation constant (Kd). And a lower dose. Ex: If an activated receptor has a high affinity, this means it will have a low dissociation constant. Correlating to a lower dose needed. If an activated receptor has a low affinity, this means it would have a high dissociation constant. Needing a high dose. Spare and Orphan receptors Spare: -Receptors that remain unbound when an agonist produces a maximal response. -If bound, can amplify the intensity and duration of a signal Orphan: -Proteins that are predicted to be receptors, but their biological ligand is not yet identified Factors affecting drug-receptor interaction -Specificity- drug to cause a certain action by binding directly to receptor -Selectivity- ability of drug to discriminate between target receptors -Affinity- Strength of attraction bw drug and receptor Specificity- (action) -Capacity of a drug to cause a particular action by binding directly to receptor High specificity= Drug has one intended effect Low specificity= responses not intended by the drug. Side effects may be the new target. Selectivity- (location) -Ability of drug to discriminate between target receptors. Choosing receptor that’s most effective. High selectivity= less adverse effects due to binding to the intended receptor and nothing else. Low selectivity= Lots of side effects. Side effects come with hitting multiple receptors. Affinity- (Strength of bind) -Strength of attraction bw drug and receptor High affinity= Low dissociation constant. Lower dose required Low affinity= High dissociation constant. Higher dose required. Agonist -Binds to and activates receptor. -Effect can be direct or indirect. Receptor activation occurs through: -Change in conformation -Incorporation of effector machinery -Linkage of a coupling molecule to a separate effector molecule -Effect can be direct or indirect Types of Agonist -Full agonist (Activates receptor-effector systems to the max) (High intrinsic activity) -Partial agonist (binds to and activates receptor but with less effect) (low intrinsic activity) (Acts as agonist if absence of full agonist) (Acts as antagonist in presence of full agonist) -Inverse agonist (Only applies to receptors with constitutive activity) (Stronger affinity for inactive state) (Stabilizes the receptor at inactive state) Antagonist -Binds to receptor but no activation Types: Competitive -Competes with agonist for receptors Noncompetitive -Allosteric inhibition -Meaning that its binding at a site other than agonist-binding domain -Induces a conformational change in receptor so that agonist no longer recognizes its binding domain Reversible -Overcome by increasing concentration of agonist Irreversible -Cannot be overcome by increasing concentration of agonist bc permanently bound to receptor -Stays antagonist no matter the concentration of agonist you try and give it. Duration of drug action -May only as long as drug occupies receptor (less common). Termination at dissociation. -May persist after drug has dissociated (more common) -May continue until drug receptor complex is destroyed (covalently bound drug-receptor complexes) -To prevent excessive activation, desensitization mechanisms in many receptor-effector systems Receptor families info -Most receptors are membrane bound proteins that transduce extracellular signals into intracellular responses Membrane bound proteins. Extracellular signals into intracellular responses. Four families -Ion channels (ligand and voltage) -G-protein-coupled receptors -Enzyme-linked receptors -Intracellular receptors Ion Channels -Ion examples: NA,CA,K,CL 2 types: (Ligand-Gated) -Extracellular portion of channel has binding site. Site controls opening of pore. -If ligand binds then the channel will open -Channel is usually closed unless this binding occurs. -Very fast. Neurons. (Voltage-gated) -Controlled by membrane potential -Depolarization when channel opens -Has a voltage sensor and a pore. Pore is where the drugs bind. G-Protein coupled receptors (GPCRs) -Largest receptor family -Known as seven-transmembrane or serpentine receptors -Intracellular portion undergoes conformational change when ligand binds. Allowing for interaction with G-protein G protein has 3 subunits -Alpha= binds to GTP -Beta and Gamma- anchor G protein in cell membrane Steps of G-protein receptor 1. When ligand binds alpha has a greater affinity with GTP 2. Dissociation of alpha-GTP complex from beta gamma complex 3. Free subunits interact with specific cellular effectors 4. Activated effector produce secondary messengers -GPCR= SECONDARY MESSENGERS G protein effectors and secondary messengers -Gs= G protein that stimulates adenylyl cyclase, which increases cAMP. (hormones) -Gi= G protein that inhibits adenylyl cyclase, which decreases cAMP. (serotonin) -Gq= G protein that activates phospholipase C, which increases IP3 and diacylglycerol Enzyme-linked receptors -Transmembrane proteins -Extracellular portion with a binding site. Intracellular portion has an enzymatic unit. -Plays a key role in cell growth, differentiation, and proliferation What happens when Enzyme-linked receptors are activated? -Undergo conformational changes that trigger a sequence of signals, leading to downstream effects. EXs: RTKs, Cytokine receptors Receptor tyrosine kinase activation: -Have intrinsic kinase activity at intracellular portion -When receptor is activated, tyrosine kinases phosphorylate the receptor -The activated enzyme-linked receptor catalyzes phosphorylation of tyrosine residues on different target signaling proteins—--signaling cascade -One activated enzyme-linked receptor affects a large number of biochemical processes -Like a molecular switch Cytokine Receptor info Structure: Extracellular and intracellular Enzymes: RTKs, Cytokine Activation: From dimer to signal phosphorylation Main idea: Signal for downstream effects. CELL GROWTH, Differentiation, Proliferation DOWNREGULATION -Intensity and duration of action of tyrosine kinases limited by down-regulation= endocytosis -Ligand binding induces accelerated endocytosis of receptors, followed by degradation. Cytokine Receptors -Similar to tyrosine kinase receptors -DIFFERENCE IS tyrosine kinase is not intrinsic to the receptor -Requires an intermediary (JAK) to phosphorylate tyrosine kinases JAK STAT -Ligands bind -cytokine receptors dimerize-Jaks activated-JAKs phosphorylate tyrosine residues on receptor. -Binds another set of proteins. STATs -STATs dimerize, dissociate from receptor -travel to nucleus -regulate transcription of specific genes Review: How are cytokine receptors different from receptor tyrosine kinases? Cytokine receptors lack intrinsic tyrosine kinase activity. Review: How are they similar? they both have a ligand-binding region on the outside of the cell and a cytoplasmic region with a protein tyrosine kinase domain Intracellular Receptors -Ligands must be sufficiently lipid soluble to cross plasma membrane and act on intracellular receptors -activate or inactivate transcription factors—Alter the transcription of DNA to RNA and translation of RNA into proteins. -Exs: Steroids- corticosteroids, sex steroids, vit D -Thyroid Hormone Two important consequences of intracellular ligand-receptor binding 1. Lag period 30 min-several hours= Time required for synthesis of new proteins. 2. Time required for synthesis of new proteins. Effects can persist for hours or days after concentration has reached zero. -Relatively slow turnover of enzymes Review: What kind of ligands bind to intracellular receptors? -Lipid soluble. Ex: steroids and thyroid How do intracellular receptors change the activity of a cell? -Alter gene expression effect transcription and translation Signal Amplification -Characteristics of G protein coupled and enzyme-linked receptors. -Activated G proteins last longer than original agonist-receptor complex -Prolongation and amplification mediated by interaction between G proteins and intracellular targets. -Only a fraction of total receptors of specific ligand need to be occupied to attain max response -Unused receptors= spare receptors 99% of insulin receptors are spare Only 5-10% of beta adrenoceptors in heart are spare Desensitization of receptors -Rapid response to an agonist, it can overstimulate receptors. -Receptors need a minute to rest (desensitization) -During that time, there can be a sudden decrease in response to drug (tachyphylaxis) Regulation of receptors Downregulation: Receptors need a finite time after stimulation before activation can occur again. Upregulation: Repeated exposure of receptor to antagonist results in up-regualtion of receptors.