Drug-Receptor Interactions Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-2 September 19, 2011

What is Drug? Chemical substance Used in the treatment, cure and diagnosis of diseases

What is Receptor? Macromolecular protein on the plasma membrane that binds the drugs and initiates its effects

Drug-Receptor Interaction Most drugs exert their effects by interacting with receptors Receptors bind drugs and initiate events leading to alterations in biochemical and/or biophysical activity of a cell

Drug-Receptor Interaction Drugs interact with receptors in many different ways, may bind to enzymes, nucleic acids, or membrane receptors The formation of the drug–receptor complex leads to a biologic response Most receptors are named to indicate the type of drug/chemical that interacts best with it Cells may have tens of thousands of receptors for certain ligands (drugs) Cells may also have different types of receptors, each of which is specific for a particular ligand The magnitude of the response is proportional to the number of drug–receptor complexes

Drug-Receptor Interaction Biologic Response

Drug-Receptor Interaction Drug-Receptor Complex Biologic Response

Drug-Receptor Interaction Drug-receptor interaction is closely related to the formation of complexes between enzyme and substrate, or antigen and antibody Receptor not only has the ability to recognize a ligand, but can also couple or transduce this binding into a response by causing a conformational change or a biochemical effect

Chemistry of Drugs and Receptors Interaction of receptors with drugs involves the formation of chemical bonds Electrostatic and hydrogen bonds, van der Waals forces These bonds are important in determining the selectivity of receptors, because the strength of these noncovalent bonds is related inversely to the distance between the interacting atoms Successful binding of a drug requires an exact fit of the drug atoms with the complementary receptor atoms The bonds are usually reversible

Chemistry of Drugs and Receptors Interaction of receptors with drugs involves The size, shape, and charge distribution of the drug molecule determines which of the binding sites in the cells of the patient can interact with Interaction of the drug with its receptor exhibits a high degree of specificity In the presence of a drug, the receptor undergoes a conformational change to bind the drug The change in conformation of the receptor caused by binding of the agonist activates the receptor, which leads to the pharmacologic effect

Types of Receptors Depending on the cellular effects receptors are 4 types: Type 1: Ligand-gated ion channels (ionotropic receptors) These are membrane proteins with a similar structure to other ion channels, and incorporate a ligand-binding (receptor) site, usually in the extracellular domain Examples: nAChR, GABAA receptors

Types of Receptors, continued….. Type 2: G-protein-coupled receptors (GPCRs) They are membrane receptors that are coupled to intracellular effectors systems via a G-protein, changes the concentration of intracellular second messenger Examples: mAChR, adrenergic receptors

Types of Receptors, continued….. Type 3: Kinase-linked and related receptors They comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix Examples: insulin, cytokines, growth factors

Types of Receptors, continued….. Type 4: Nuclear receptors These are receptors that regulate gene transcription The term nuclear receptors is something of a misnomer, because some are actually located in the cytosol and migrate to the nuclear compartment when a ligand is present Examples: steroid hormones, thyroid hormone

Second Messenger Second messengers are essential in conducting and amplifying signals coming from GPCRs G protein activates adenylate cyclase, which converts ATP to cAMP. cAMP is one of the second messenger that regulates protein phosphorylation G proteins also activate phospholipase C, which is responsible for the generation of two other second messengers, inositol-1,4,5-trisphosphate (IP3) and diacylglycerol G protein activates guanylate cyclase, which converts GTP to cGMP, a fourth second messenger that stimulates protein kinase

Structure-Activity Relationship (SAR) Interaction between a drug and its receptor is defined as affinity of the drug for the receptor Affinity is determined by the chemical structure Minor changes in the drug molecule may result in major changes in pharmacological properties SAR led to the synthesis of valuable therapeutic agents

Desensitization of Receptors Repeated administration of a ligand (drug) may lead to changes in the responsiveness of the receptor Repeated administration of a drug results in a diminished effect, the receptor becomes desensitized to the action of the drug In this phenomenon, the receptors are still present on the cell surface but are unresponsive to the ligand Other types of desensitization occur when receptors are down-regulated