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

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

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

4. 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

5. 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

6. Drug-Receptor Interaction
Biologic Response

7. Drug-Receptor Interaction
Drug-Receptor Complex
Biologic Response

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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