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Pharmacology-1 PHL 351 Abdelkader Ashour, Ph.D. Third Lecture Drug Receptors Receptor/Binding site “A specific protein in either the plasma membrane or interior of a target cell with which a ligand/drug combines” It must be selective in choosing ligands/drugs to bind To avoid constant activation of the receptor by promiscuous binding of many different ligands It must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered This is necessary for the ligand to cause a pharmacologic effect Orphan receptors “Receptors for which no ligand has been discovered and whose function can only be presumed” Drug Receptors Receptor/Binding site “A specific protein in either the plasma membrane or interior of a target cell with which a ligand/drug combines” It must be selective in choosing ligands/drugs to bind To avoid constant activation of the receptor by promiscuous binding of many different ligands It must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered This is necessary for the ligand to cause a pharmacologic effect Orphan receptors “Receptors for which no ligand has been discovered and whose function can only be presumed” Drug Receptors Receptor/Binding site “A specific protein in either the plasma membrane or interior of a target cell with which a ligand/drug combines” It must be selective in choosing ligands/drugs to bind To avoid constant activation of the receptor by promiscuous binding of many different ligands It must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered This is necessary for the ligand to cause a pharmacologic effect Orphan receptors “Receptors for which no ligand has been discovered and whose function can only be presumed” Specificity “The ability of a receptor to bind only one type or a limited number of structurally related types of ligands/drugs” Drug Receptors, contd. Down-regulation “A decrease in the total number of target-cell receptors for a given messenger/ligand in response to chronic high extracellular concentration of the messenger/ligand” Up-regulation “An increase in the total number of target-cell receptors for a given messenger/ligand in response to a chronic low extracellular concentration of the messenger/ligand” Supersensitivity “The increased responsiveness of a target cell to a given messenger/ligand, resulting from up-regulation” Drug Receptor Interactions The Lock and Key Model of Signal-Receptor Interaction Ligands such as hormones or neurotransmitters (the"key") affect target cells by binding to specific receptors (the "lock”), which are often located in the cell membrane This binding "unlocks" the cell's response, so that the hormone or neurotransmitter can exert its effects Agonist “A chemical messenger that binds to a receptor and triggers the cell’s response; often refers to a drug that mimics a normal messenger’s action”. For example, pilocarpine is a muscarinic receptor agonist because it can bind to and activate muscarinic receptors Antagonist "A molecule that competes for a receptor with a chemical messenger normally present in the body. The antagonist binds to the receptor but does not trigger the cell’s response” For Example, atropine is a muscarinic receptor antagonist because it prevents access of acetylcholine and similar agonist drugs to the acetylcholine receptor Drug Receptor Interactions Lock and key mechanism Agonist Receptor Agonist-Receptor Interaction Drug Receptor Interactions Competitive Inhibition Antagonist Receptor DENIED! Antagonist-Receptor Complex Drug Receptor Interactions Non-competitive Inhibition Agonist Antagonist Receptor DENIED! ‘Inhibited’-Receptor Drug Receptor Interactions, contd. Affinity The extent to which the ligand/drug is capable of binding and remained bound to receptor. High Affinity – the ligand binds well and remains bound long enough to activate the receptor. Low Affinity – the ligand binds less well and may not remain bound long enough to activate the receptor. High Affinity Drug Receptor Interactions, contd. Affinity The extent to which the ligand/drug is capable of binding and remained bound to receptor. High Affinity – the ligand binds well and remains bound long enough to activate the receptor Low Affinity – the ligand binds less well and may not remain bound long enough to activate the receptor Low Affinity Dose-Response Functions Biological Effect Displays the relationship between the dose of a ligand and some biological response to that ligand Dose-Response Functions, contd. Efficacy (Emax) The maximal response that the drug can produce. It is the effect that is observed at saturating concentrations Agonists will have high efficacy, whereas antagonists will, generally, have zero efficacy EC50/ED50 The concentration or dose of the drug that is needed to produce a 50% maximal response (A) Red (B) Which drug has more efficacy? And why? Dose-Response Functions, contd. Potency The amount (weight) of drug in relation to its effect. For example, if the weight-for-weight drug A has a greater effect than drug B drug A is more potent than drug B, although the maximum therapeutic effect may be similar with both drugs Drugs of high potency will generally have a high affinity for the receptors and thus occupy a significant proportion of the receptors even at low concentrations Dose-Response Functions, contd. Biological Effect Efficacy & Potency A B Which drug has more efficacy? Which drug has more potency? And why? Efficacy: A=B Potency: A>B Dose-Response Functions, contd. Biological Effect Efficacy & Potency A B Which drug has more efficacy? Which drug has more potency? And why? Efficacy: A>B Potency: A=B Dose-Response Functions, contd. Biological Effect Efficacy & Potency A B Which drug has more efficacy? Which drug has more potency? And why? Efficacy: A>B Potency: A>B