PHL 211 Pharmacology Sixth Lecture By Abdelkader Ashour, Ph.D. Phone:
Types of Targets for Drug Action E.Others like structural proteins such as tubulin, which specifically binds colchicine Other non-protein drug targets such as: DNA: antimicrobial and anti-tumor drugs interact directly with DNA RNA: such as ribavirin against HCV A.Receptors e.g., receptors targets for adrenaline B.Ion Channels e.g., Na channel of excitable membranes target for local anesthetics C.Enzymes e.g., cyclooxygenase target for NSAIDs (e.g., aspirin) D.Carriers/transporters e.g., norepinephrine carrier target for maprotiline
Drug Mechanisms (How Drugs Act?) I.Receptor mechanisms: Most drugs exert their effects by binding to receptors This has the effect of either mimicking the body’s own (endogenous) substances binding to receptors or preventing their binding or actions II.Non-receptor mechanisms: These include: 1.Changing Cell Membrane Permeability (Ion Channels) 2.Actions on enzymes 3.Carrier Molecules, e.g. uptake proteins 4.Changing Physical Properties 5.Combining with Other Chemicals 6.Anti-Metabolites
Receptors Serve as recognition sites for specific endogenous compounds such as: 1. Neurotransmitters, e.g. noradrenaline (NA) 2. Hormones, e.g. adrenaline (released from the adrenal medulla and acts on the heart) 3. Local Hormones /Autacoids (released and act upon the same/nearby tissue, e.g. prostaglandins) Receptor-Effector Coupling -When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacologic response. -The transduction process between occupancy of receptors and drug response is often termed coupling.
Receptor Family, Summary and Examples
Action Potential Depolarization Repolarization
1. Ligand-gated Ion Channels They incorporate a ligand-binding (a receptor) site, usually in the extracellular domain and they are activated by binding of a ligand (agonist) to the receptor on the channel molecule Binding of the agonist causes a conformational change in the receptor which leads to ion channel opening Involved in fast synaptic transmission They control the fastest synaptic events in the nervous system, in which neurotransmitter acts on the postsynaptic membrane of a nerve or muscle cell and transiently increases its permeability to particular ions Example: nACh receptor
2. G-protein-Coupled Receptors (GPCRs) The largest family: G-protein (guanine nucleotide binding regulatory proteins) families: G s, G i and G q Examples: mAChR, adrenoceptors, glutamate receptors, GABA B receptors Actions: fast (seconds) Structure: GPCR consists of seven transmembrane -helices G-protein consists of 3 subunits, , , . Guanine nucleotides bind to the -subunit which has GTPase activity (GTP GDP) The and subunits remain together as , -complex
2. G-protein-Coupled Receptors “The activation of the effector tends to be self-limiting” GTPase?? Amplification? Mechanism: binding of the agonist to the GPCR activation of the GPCR G- protein activation (G-GDP G-GTP) : Activation or inhibition of enzyme with subsequent modification of second messenger level (e.g. cAMP, IP3) → biological effect or Opening or closing of an ion channel (Inactive) (Active) Opposite functional effects may be produced at the same cell type by GPCRs (e.g., mAChR and -adrenoceptors in cardiac cells)
2. G-protein-Coupled Receptors, Targets PIP2: phosphatidylinositol- 4,5-bisphosphate IP3: inositol-1,4,5- trisphosphate DAG: 1,2-diacylglycerol PIP2 GqGq