DRUG RECEPTOR INTERACTION. LECTURE 4 PHARMACOLOGY. Drug Receptors and Pharmacodynamics. The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action. Receptors Definitions Classification Ligands (Drugs)
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DRUG RECEPTOR INTERACTION LECTURE 4 PHARMACOLOGY
Drug Receptors and Pharmacodynamics The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.
Receptors • Definitions • Classification • Ligands (Drugs) • Ligand-Receptor interaction • Interaction and consequence • Receptor-mediated mechanism of action
Drug Binding Sites(Receptors and Acceptors) • Binding Site • Specific and Saturable • Receptor • Binding Site + Effect • Acceptor • Binding Site + no Effect
DRUG TARGETS • many drugs inhibit enzymes • Enzymes control a number of metabolic processes • A very common mode of action of many drugs • in the patient (ACE inhibitors) • in microbes (sulfas, penicillins) • in cancer cells (5-FU, 6-MP) • some drugs bind to: • proteins (in patient, or microbes) • the genome (cyclophosphamide) • microtubules (vincristine)
most drugs act (bind) on receptors • in or on cells • form tight bonds with the ligand • exacting requirements (size, shape, stereo specificity) • can be agonists (salbutamol), or antagonists (propranolol) • receptors have signal transduction methods
enzyme linked • (multiple actions) • ion channel linked • (speedy) • G protein linked • (amplifier) • nuclear (gene) linked • (long lasting) Signal transduction
Drug Receptor • A macromolecular component of a cell with which a drug interacts to produce a response • Usually a protein
Types of Protein Receptors • Regulatory – change the activity of cellular enzymes • Enzymes – may be inhibited or activated • Transport – e.g. Na+ /K+ATPase • Structural – these form cell parts
B. Second Messengers • Small, nonprotein, water-soluble molecules or ions • Readily spread throughout the cell by diffusion • Two most widely used second messengers are: • 1. Cycle AMP • 2. Calcium ions Ca2+
2. Calcium Ions (Ca2+) and Inositol Trisphosphate • Calcium more widely used than cAMP • used in neurotransmitters, growth factors, some hormones • Increases in Ca2+ causes many possible responses: • Muscle cell contraction • Secretion of certain substance • Cell division
Two benefits of a signal-transduction pathway • 1. Signal amplification • 2. Signal specificity • A. Signal amplification • Proteins persist in active form long enough to process numerous molecules of substrate • Each catalytic step activates more products then in the proceeding steps
Receptors and Drug Action • Receptors: • Specific areas of cell membranes (proteins, glycoproteins)* • When bound to ligand, positive or negative biological response Few ex. of free receptors in cytoplasm
Drugs that do act on receptors: Drugs that do not act on receptors: Antacids: CaCO3 + HCl Diuretics (osmotic) Alkylating agents (cancer) Psoralenes Agonist: Binds to (have affinity for) receptor Binding leads to biolog. response (Agonists have intrinsic activity / efficacy) Antagonist: Affinity for receptor No intrinsic activity
Types of receptors-Mechanism of Action Super- Endogenous General structures family ligands 1 Fast neurotransmitters Ligand gated ion channels ex. Acetylcholine 2 Slow neurotransmitters. ex. noradrenalin G-Protein coupled receptors Hormones 3 Insulin Enzyme coupled receptors Growth factors Catalytic receptors 4 Steroid hormones Cytoplasmic receptors Thyroid hormones Vitamin A, D
Ligand gated ion channels Ligands Fast neurotransmitters ex. Acetylcholine (nicotinic receptors) Fastest intracellular response, ms Binding of ligand - opening of channel - ion (K+, Na+) in or out of cell - response Nobel prize chemistry 2003, Roderick MacKinnon“for structural and mechanistic studies of ion channels”. http://nobelprize.org/chemistry/laureates/2003/press.html
G-Protein coupled receptors G-protein: Guanine nucleotide binding protein
Subtypes of G-proteins - Targets (Second messenger systems) • Ion channels: G12 Na+ / H+ exchange • Enzymes: Gi Inhib. Adenylyl cyclase • Gs Stimul. Adenylyl cyclase • Gq Stimul. Phospholipase C • One ligand can bind to more than one type of G-protein coupled receptors second messenger pathways
Subtypes of G-proteins - Targets (Second messenger systems) • Ion channels: G12 Na+ / H+ exchange • Enzymes: Gi Inhib. Adenylyl cyclase • Gs Stimul. Adenylyl cyclase • Gq Stimul. Phospholipase C second messenger pathways
Structure: • Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices • There’s a G protein attached to the cytoplasmic side of the membrane (functions as a switch). G protein-linked receptors
Enzyme coupled receptors - Catalytic receptors Ligands: Peptide hormones STAT:Signal transducers and activators of transcription
Ion channel receptors • Structure: • Protein pores in the plasma membrane
Cytoplasmic receptors (not bound to cell membranes) (HSP-90: Heat shock protein)
Intracellular receptors Not all signal receptors are located on the plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cells. • The signal molecule must be able to pass through plasma membrane. Examples: ~Nitric oxide (NO) ~Steroid (e.g., estradiol, progesterone, testosterone) and thyroid hormones of animals).
Nuclear Receptors • Examples: • Glucocorticoids: Inhibit transcription of COX-2; induce transcription of Lipocortin • Mineralcorticoids: Regulate expression of proteins involved in renal function • Retinoids (Vit A derivatives): Control embryonic development of limbs and organs; affect epidermal differentiation => dermatological use (Acne) • PPARs (Peroxisome Proliferation-Activated Receptors): control metabolic processes: • PPARa: Target of Fibrates (cholesterol lowering drugs: stimulate b-oxidation of fatty acids) • PPARg: Target of Glitazones (anti-diabetic drugs: induce expression of proteins involved in insulin signaling => improved glucose uptake)
Tyrosine-kinase receptors • Structure: • Receptors exist as individual polypeptides • Each has an extracellular signal-binding site • An intracellular tail with a number of tyrosines and a single å helix spanning the membrane
Receptor subtypes Most receptor classes - several sub-types Each subtypes - differend A(nta)gonists Sub types cholinergereceptors Muscarinergic receptors Nicotinerge receptors M1: G-Protein coupled receptors Stimulate phospholipase A M2: G-Protein coupled receptors Inhib. adenylyl cyclase Nmuscle: Ligand gated ion channels Incr. Na+/Ca2+ Nneuro: Ligand gated ion channels Incr. Na+/Ca2+
Binding of ligand to receptor • Covalent bond • Ionic bond • Hydrogen bond • Hydrophobic interaction Covalent bond strong; 50-150 kcal/mol, Normally irreversible bonding ex. Acetylcholine esterase inhibitors
Reversible inhibitors AcCh Inhibitor Reversible inhibitor (drugs): k3 (inhib) < k3(AcCh) Neostigmine Pyridostigmine Myasthenia gravis (weak muscles, reduced sensitivity to Acetylcholine)
Irreversible Inhibitors Not drugs, nerve gasses, insecticides etc.
Ionic bond 5-10 kcal/mol, Reversible bonding Hydrogen bond 2-5 kcal/mol, Reversible bonding Hydrophobic interaction 0.5-1 kcal/mol, Reversible bonding
The occupancy theory: The more receptors sites occupied by ligand, the stronger response The rate theory: The more ligand-receptor interact / unit time, the stronger response The induced-fit theory: The macromolecular pertubation theory: (induced fit + rate theory)
The activation -aggregation theory: Always dynamic equilibrium.
Dose-Response Relationships R locked in membrane (do not move freely) L dissolved in extracellular fluid Reaction on solid - liquid interface
Ligands(Receptor binding molecules) • Drugs or endogenous compounds binding to receptors are described as Ligands. • Ligands are classified into 2 groups • Agonist: molecule that binds to receptor and produces similar response to that of the endogenous ligand • Partial agonist agonist that produce partial effect • Antagonist: molecule that binds to a receptor, but does not cause a response • Competitive reversible or weak binding • Non-competitive non-reversible or strong binding
Affinity and Efficacy • Affinity: the attraction of the drug for the receptor. • high affinity: low concentrations bind • low affinity: high concentrations bind • no affinity: does not bind • Efficacy: the intrinsic activity • Max. effect efficacy = 1 • Min. effect efficacy = 0
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