FFP1-58 Agonists STS 2023 (2).pptx

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-58 Drug Receptor Interactions: Agonists Prof Steve Safrany 341 [email protected] Dr. Roger Preston Learning outcomes • Define the terms ‘ligands’ and ‘receptors’ • Describe the way in which receptors are define...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-58 Drug Receptor Interactions: Agonists Prof Steve Safrany 341 [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 receptor Modified activated Substrate + enzyme substrate Modified Different types of receptor ligand agonis t ligan d recept or recept or Respons e? Ligand - a chemical that selectively binds to a receptor antagoni st respon se Agonist - a ligand which binds to a receptor and causes a biological recept or No response Antagonist binds to a receptor but has no effect and prevents other ligands What is a receptor? • Receptors possess affinity for its endogenous ligand at physiological concentrations • Receptors are saturable and finite (limited number of binding sites) • Once the endogenous ligand binds to the How do ligands bind selectively to receptors? • Receptor structure has evolved over time to recognise specific ligands • Often more than one ligand and different ligands can promote different receptor signalling • Also, one receptor expressed in different tissue The dose-response relationship • The more occupied receptors, the bigger the signaling response • Dose-response curve – ED50 120 110 Heart rate (bpm) • Tissue responses are generally directly proportional to the fraction of the receptors occupied with agonist 100 90 80 70 0 20 40 60 80 100 ED50 Adrenaline (ng/Kg/min) Concentration-response curve 80 Response (%) EC50: Effective concentration, 50% 100 60 40 [agonist] giving 50% of its maximum response 20 0 0 100 EC50 200 300 400 [Agonist] (nM) 500 Log concentrationresponse curve Response (%) 100 80 60 40 Log EC EC5050 20 0 1 -6 10 100 1000 [Agonist] (µM) -5 -4 Log[agonist] -3 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 How do you measure drugs binding to receptors? Bmax Maximum binding = number of receptors in the system Kd Equilibrium dissociation constant = [drug] binding to 50% of receptors Using log concentration-binding curves to measure drug binding to receptors con cen trat Interpretation of Dosei on response curves: Binding (%) 100 80 • similar to MichaelisMenten kinetics 60 40 20 0 Kd 10 91 8 710 0 -log [Agonist] liga nd • Called Langmuir equation • normally displayed as i on t a r t n e c n co Log-Dose/ Response curves 1000 6 • Allows us to measure drug affinity (Kd) (nM) and maximal How do you measure drugs binding to receptors? IC50 From IC50, we can calculate Ki Ki = IC50/(1+ [L]/Kd) How do we calculate drug potency? • Expressed in terms of the amount required to produce an effect of given intensity • E.g., 50% of its maximal response Potency dose Response (%) • Potency is a measure of drug activity Emax 100 80 A 60 B C 40 20 0 1 10 100 1000 [Agonist] µM Isoprenaline (A) 20 μM > Adrenaline (B) 80 μM > Noradrenaline (C) 300 μM 10000 What is a ‘partial agonist’? • Some agonist never produce maximum response • Known as partial agonists • Full agonist – receptor goes from being ‘OFF’ • to Partial ‘ON’ agonists can be on, without exerting maximal 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 less than 1 • Partial agonists will still occupy all the Efficacy Everest α=1: Full agonist 1>α>0: Partial agonist α=0: antagonist Full versus partial agonists Full agonis t Partial agonist recept or conformational change FULL respon se Agonist - a ligand which binds to a receptor and causes a biological response recept or REDUCED conformational change REDUC ED respons e Partial agonist - a chemical that binds to a receptor, but induces reduced signalling 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 What is the difference between ‘efficacy / intrinsic activity’ and ‘potency’? Potency dose 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 Efficacy Everest Although Drug C has lower efficacy than B, It 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 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 • K d , Ki K no • Dose – amount given w yo u r • Concentration – amount per unit volume u ni • EC50, IC50 ts • Potency • Efficacy / intrinsic activity • ED50 • 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]