Pharmacology - Agonists (RCSI FFP1-58) 2024 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-58 Drug Receptor Interactions: Agonists Prof Will Ford 337 [email protected] Dr. Roger Preston ...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-58 Drug Receptor Interactions: Agonists Prof Will Ford 337 [email protected] Dr. Roger Preston  Learning outcomes Define the terms ‘ligands’ and ‘receptors’ Describe the way in which receptors are defined Explain the concept of a dose-response relationships Explain quantitative concepts [Kd; Bmax; IC50 / EC50]  Receptor-ligand interactions Analogous to enzyme substrate interactions: “Drugs do not act unless bound” (Paul Ehrlich, 1913) Many drugs bind to receptors  Receptors and enzymes Drug + target Effect Ligand + receptor Modified receptor activated Substrate + enzyme Modified substrate Different types of receptor  What is a receptor? Receptors possess affinity for ligands Receptors are saturable and finite (limited number of binding sites) Receptors are discontinuously distributed Agonist binding to a receptor causes a response The same receptor may generate a different physiological response in different tissues  How do ligands bind selectively to receptors?  Selectivity defined as relative affinity.  Ligand-receptor binding is not specific a ligand will bind to other receptors as the dose/concentration is increased – see therapeutic index xample: β1- and β2-adrenoceptor subtypes in the heart Stimulation of cardiac β1 adrenoceptors increases heart rate (HR) Stimulation of cardiac β2 adrenoceptors increases coronary flow (CF)  The dose-response relationship Tissue responses are generally directly 120 proportional to the 110 fraction of the Heart rate receptors occupied 100 with agonist (bpm) 90 The more occupied receptors, the bigger 80 the signaling response 70 0 20 40 60 80 100 Dose-response ED50 curve – ED50 Adrenaline (ng/Kg/min) Linear versus log dose-response curves 100 % Maximum } Tissue Response Linear Threshold ED50 ED50 Log Dose [A] Linear scale Log scale Sub-threshold concentration Effective concentration 50% (EC50) Maximum response  How do you assess how drugs interact with receptors? Functional studies Measure response of tissue to drug Binding studies Directly measure the binding of radiolabeled drug to tissue. Ligand only?  Necessary assumptions… Ligands bind specifically and reversibly to a receptor Binding is SATURABLE (at a certain concentration no more binding is possible) and REVERSIBLE All receptors are equally accessible to ligands Receptors are EITHER (i) free or (ii) bound to drug SATURATION BINDING - PRINCIPLES Radioactive ligand R Receptor P Membrane protein Unbound label WASH P R R TOTAL BINDING SPECIFIC BINDING NON-SPECIFIC BINDING SPECIFIC BINDING Only interested in binding to the receptor (specific) Specific binding is SATURABLE – i.e. there is an upper limit – the number of receptors present Non-specific binding is non-saturable – i.e. will always increase with increasing addition of ligand Total binding = specific binding + non-specific binding How can specific binding be worked out from this? NON-SPECIFIC BINDING Radioactive ligand R Receptor P Membrane protein ‘cold’ ligand WASH P R R Non-specific binding remains SATURATION BINDING ANALYSIS Radioactivity Total Specific = total – non-specific Max specific binding Specific Non-specific 50% specific binding KDConcentration of radioligand COMPETITION BINDING Add ONE concentration of radioligand Displace radioligand from receptors with unlabelled ligand Radioligand and ‘cold’ ligand can be the same Affinity is calculated based on the RELATIVE affinities and concentration of radioligand used  ANALYSIS OF COMPETITION BINDING 1  D * K A* KA  IC 50 Radioactivity You do not need Specific IC50 to learn this formula Non-specific Concentration of ‘cold’ ligand  How do we calculate drug potency? Potency is a Emax measure of drug 100 Response (%) activity 80 60 Expressed in A B C 40 terms of the 20 amount required 0 to produce an 1 10 100 1000 10000 effect of given [Agonist] µM intensity Isoprenaline (A) 20 μM > E.g., 50% of its Adrenaline (B) 80 μM > Noradrenaline (C) 300 μM maximal response  What is a ‘partial agonist’? Efficacy or intrinsic activity (α) is the ability to produce a response Partial agonists exhibit efficacy of greater than 0, but α=1: Full agonist less than 1 1>α>0: Partial agonist Partial agonists will α=0: antagonist still occupy all the  Full versus partial agonists Full Partial agonis agonist t recept recept or or conformational REDUCED conformational change change FULL REDUC respon ED se respons e Agonist - a ligand which Partial agonist - a chemical binds to a receptor and that binds to a receptor, but causes a biological induces reduced signalling response response  Example of partial agonism: ‘Painkillers’ - Opioid receptors Opioid receptors –GPCRs important for pain transmission and neurotransmission Opioids are agonists for mu opioid receptors Full agonists include fentanyl, morphine, methadone Partial agonists include buprenorphine, codeine*, butorphanol**, and  Example of partial agonism: Nicotine Replacement Therapy Blocking or desensitizing nicotinic receptors prompts greater receptor expression on neurons Nicotinic partial agonists (e.g., varenicline)  Difference between varenicline & nicotine 100 100 No tobacco No tobacco 80 Nicopatch 80 Var alone % Max reward % Max reward NP with cigarette Together 60 60 40 40 20 20 0 0 0 50 100 150 200 250 0 50 100 150 200 250 Time (hours) Time (hours)  What are ‘spare receptors’? Maximum signalling response often observed without full occupancy of available receptors Receptors are ‘spare’ whenever maximum response at less than full agonist binding Has the effect of increasing tissue sensitivity to agonists Presence of spare receptors mean it is possible to get a What is the difference between ‘efficacy / intrinsic activity’ and ‘potency’? Drug A has GREATER POTENCY than Drug B, but SAME POTENCY as Drug C Drug A and Drug B have the SAME EFFICACY as each other, BOTH have GREATER EFFICACY than Drug C Although Drug C has lower efficacy than B, It  1. Summary – New terminology Ligand – Binds its target Receptor – Next week Agonist – Full – Partial Antagonist – Next lecture  2. Summary – New terminology Affinity – the ability to bind a target Kd , K i K no Dose – amount given w ED50 yo ur Concentration – amount per unit volumeu EC , IC ni 50 50 ts Potency Efficacy / intrinsic activity Partial agonists Spare receptors  What we have learned… Define the terms ‘ligands’ and ‘receptors’ Describe the way in which receptors are defined Explain the concept of a dose-response relationships Explain quantitative concepts [Kd; Bmax; IC50 / EC50]