PHL 210 Pharmacology Second Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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 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

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

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 Drug In order to interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition Orphan receptors “Receptors for which no ligand has been discovered but they have a similar structure to other identified receptors and whose function can only be presumed” If a ligand for an orphan receptor is later discovered, the receptor is referred to as "adopted orphan receptor"

Drug Receptors, contd. Receptor Down-regulation Desensitization “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” Desensitization “The loss of a drug’s effect, when it is given continuously or repeatedly, on a short time-scale” Often results from receptor down-regulation Receptor 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 receptor up-regulation”

Drug Receptor Interactions Agonist “A chemical messenger (or drug) 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 can bind to muscarinic receptors but it does not trigger the cell’s response. In this way, it prevents binding of acetylcholine (ACh) and similar agonist drugs to the ACh receptor

The Lock and Key Model of Signal-Receptor Interaction Drug Receptor Interactions The Lock and Key Model of Signal-Receptor Interaction Ligands such as hormones, neurotransmitters or drugs (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

Drug Receptor Interactions Lock and key mechanism Agonist Receptor Agonist-Receptor Interaction

Drug Receptor Interactions Competitive Inhibition Antagonist Receptor Antagonist-Receptor Complex DENIED!

Drug Receptor Interactions Non-competitive Inhibition Antagonist Agonist 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