Receptors and Drug Channels PDF

Foundations of Pharmacology PHAR2210 Receptors and other Drug Targets A/Prof Lynette Fernandes These lecture slides and associated unit materials are the intellectual property of A/Prof Lynette Fernandes and should not be shared without her permission. Sh...

Foundations of Pharmacology PHAR2210 Receptors and other Drug Targets A/Prof Lynette Fernandes These lecture slides and associated unit materials are the intellectual property of A/Prof Lynette Fernandes and should not be shared without her permission. Sharing course materials without permission breaches UWA’s student conduct regulations and may constitute a breach of the Copyright Act 1968.  Learning outcomes For each of the 4 receptor superfamilies, describe the following major characteristic features – mechanism of signal transduction – receptor location – effector protein(s) – time scale of action – agonists Explain the role of ion channels, enzymes, and transporters as drug targets Identify examples of drugs used at various targets  Resources Pharmacology Education Project https://www.pharmacologyeducation.org/pharmacology/pharmacodynamics Selected figures on the LMS from Goodman and Gilman’s The Pharmacological Basis of Therapeutics 13th edition 2017 McGraw-Hill Education. Pharmacodynamics: Molecular Mechanisms of Drug Action. Chapter 3 Rang and Dale’s Pharmacology, 10th edition 2024, London Elsevier. How drugs act: Molecular aspects.  “A drug will not work unless it is bound” Paul Ehrlich (1854-1915) Most drugs produce their effects by binding to protein targets – receptors – ion channels – enzymes – transporters or carrier molecules  Receptor superfamilies Receptors sub-divided into 4 major types or superfamilies 1. ion channel receptors 2. G protein-coupled receptors 3. enzyme-linked receptors 4. nuclear receptors  Receptor superfamilies Superfamilies are distinguished – based on how they transduce the signal – NOT on which chemical signals stimulate them – NOT on the nature of the change in cell function Receptors within a particular superfamily use similar transduction processes and so tend to have similar general structures  Ion channel receptors drug Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Ion channel receptors Located in the cell membrane Collection of proteins form central pore / channel No agonist, ion channel closed, no ion flow nicotinic acetylcholine closed ion channel receptor Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Ion channel receptors Ions cannot cross the cell membrane ACh binding alters ion channel structure and ions flow into the cell nicotinic acetylcholine receptor ACh ACh Na+ Na+ closed ion channel open ion channel Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Ion channel receptors subunit unfolded protein structure membrane Rang and Dale’s Pharmacology, 2024 location of receptor: membrane effector: channel respond to: fast neurotransmitters time scale of action: milliseconds, very fast example: nicotinic acetylcholine receptor Pancuronium, a nicotinic acetylcholine receptor antagonist, is used to produce paralysis during anaesthesia G protein-coupled receptors drug Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  G protein-coupled receptors membrane Rang and Dale’s Pharmacology, 2024 location of receptor: membrane 7 transmembrane domains effector: enzyme or channel respond to: hormones, slow neurotransmitters time scale of action: seconds, fast examples: adrenoceptors, muscarinic acetylcholine receptors Salbutamol, a b2-adrenoceptor agonist relieves bronchospasm in asthma  G proteins G proteins – intracellular effector systems or 2nd messenger cascades – guanosine nucleotide binding proteins, GTP and GDP – comprise 3 subunits (a, b, g) Main classes of Ga protein 1. Gas activates adenylate cyclase 2. Gai inhibits adenylate cyclase 3. Gaq activates phospholipase C G proteins link GPCRs to effector proteins that generate intracellular second messengers – (Gas) adenylate cyclase generates cAMP – (Gaq) phospholipase C generates inositol trisphosphate and diacylglycerol GPCR activation: airway smooth muscle RELAXATION (effect) cyclic AMP (2nd messenger) adenylate cyclase (transduction/effector protein) s Gs (stimulatory G protein) b2-adrenoceptor (receptor) salbutamol (agonist) Rang and Dale’s Pharmacology, 2024 Enzyme-linked receptors drug Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Enzyme-linked receptors membrane enzyme (e.g., kinase which phosphorylates proteins) Rang and Dale’s Pharmacology, 2024 location of receptor: membrane effector: enzyme respond to: metabolism, growth, differentiation time scale of action: minutes, slow examples: insulin receptor, receptors for cytokines, growth factors In diabetes, insulin is used to activate the insulin receptor, reducing blood glucose levels  Insulin receptor tyrosine kinase intracellular proteins Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Nuclear receptors drug Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Nuclear receptors Rang and Dale’s Pharmacology, 2024 location of receptor: intracellular effector: gene transcription respond to: steroid hormones, other factors time scale of action: hours, very slow examples: glucocorticoid, other steroid hormones Glucocorticoid drugs such as prednisolone are effective anti-inflammatory agents  Glucocorticoid receptor (cortisol) Principles of Pharmacology. D.E. Golan. Lippincott Williams & Wilkins. 2005  Protein targets for drug action Receptors Ion channels – effect of drugs? Enzymes – effect of drugs? Transporters – effect of drugs?  Receptors as drug targets Agonists bind to and activate receptors Antagonists bind to, but do not activate receptors Agonist Antagonist Rang and Dale’s Pharmacology, 2024  Ion channels as drug targets Blockers physically plug the ion channel – nifedipine is a Ca2+ channel blocker used to treat hypertension Modulators bind to accessory sites and modulate channel activity – benzodiazepines enhance GABA-activated Cl- channel opening, used to treat anxiety Blocker Modulator Rang and Dale’s Pharmacology, 2024  Enzymes as drug targets Substrate analogues competitively inhibit the enzyme – analgesics like paracetamol inhibit cyclooxygenase Inhibitor False substrate Pro-drug Rang and Dale’s Pharmacology, 2024  Enzymes as drug targets Some drugs act as false substrates for enzymes – anti-cancer drug fluorouracil replaces uracil in purine biosynthesis, blocking DNA synthesis Inhibitor False substrate Pro-drug Rang and Dale’s Pharmacology, 2024  Enzymes as drug targets Pro-drugs must be enzymatically converted to become active – ciclesonide is converted to the active metabolite in the lung, resulting in fewer adverse effects in non-airways Inhibitor False substrate Pro-drug Rang and Dale’s Pharmacology, 2024  Transporters as drug targets Specific carrier proteins transport ions and small organic molecules across cell membranes – glucose, amino acids, neurotransmitters, Na+, Ca2+ etc. Some drugs inhibit transporters – anti-depressant drug fluoxetine inhibits the re-uptake of the neurotransmitter serotonin into neurones Normal transport Inhibitor Rang and Dale’s Pharmacology, 2024  Transporters as drug targets False substrates – CNS stimulant amphetamine uses the noradrenaline transporter to enter nerve terminals and replace/release the neurotransmitters noradrenaline and serotonin Normal transport False substrate Rang and Dale’s Pharmacology, 2024