Receptor Pharmacology (Agonists) PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Title Receptor Pharmacology (Agonists) Code FPI Course Fundamentals of Pharmacology and Immunology L...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Title Receptor Pharmacology (Agonists) Code FPI Course Fundamentals of Pharmacology and Immunology Lecturer Dr Judith Coppinger Email: [email protected] Enter subtitle here (24pt, Arial Regular) Date 24th January 2025 Enter date: 25.06.13 After this lecture you will be able to…. Define the terms 'ligands' and 'receptors’ Describe the way in which receptors are defined (characteristics) Explain the concept of a dose-response relationships Explain quantitative concepts [Kd; Bmax; IC50/EC50] Define 'agonists'; 'partial agonists'; 'intrinsic activity’ Discuss the mechanism by which partial agonists work for the different receptor types RECEPTORS “Drugs do not act unless bound” (Paul Ehrlich, 1913) Drugs can act on several target e.g. some drugs bind to enzymes and inhibit them (aspirin) Most drugs bind to receptors A receptor is a molecule to which a drug binds to bring about change in function of the biological system LIGANDS A ligand is a chemical which specifically binds to a receptor The body produces natural ligands that binds receptors An agonist is a ligand which binds to a receptor and causes a biological response An antagonist binds to a receptor and has no effect but can prevent other ligands from binding CHARACTERISTICS OF A RECEPTOR Receptors first defined in early 1900s by Paul Ehrlich Receptors possess structural and steric specificity Receptors are expressed in select tissues Receptors are saturable and finite (limited number of binding sites) Receptors possess high affinity for its endogenous ligand at physiological concentrations Once the endogenous ligand binds to the receptor, a biochemical event occurs  RECEPTOR SPECIFICITY 1. Receptor specificity can be due to the characteristics of the binding site e.g. Histamine Receptor (H1) to the right Green: H1-receptor Yellow: Doxepin (H1-antagonist) Specificity is due to the size, shape and charge of binding pocket Nature 475, 65–70, 2011 2. Receptors show a high degree of specificity for their ligands example- Adrenaline (epinephrine) acts on 1-adrenoreceptors in the heart to increase the rate and force of cardiac contraction.  BIOLOGICAL RELEVANCE Receptors have normal physiological roles They are usually hormone/neurotransmitter receptors Drugs are selective for receptors Ligand-Receptor Interactions Analogous to enzyme substrate interactions Lock: Enzyme/receptor Key: Substrate/hormone/drug RECEPTOR-RESPONSE PATHWAY  RECEPTOR-RESPONSE PATHWAY Katzung &Trevor- Basic and Clinical Pharmacology 11 th edition 1. Intracellular Receptor (steroid-ER) 2. Transmembrane Receptors (EGFR) –intrinsic tyrosine kinase activity 3. Transmembrane Receptors (JAK-STAT)-activate seperate tyrosine kinase enzymes 4. Ligand gated ion channels (nACH-nicotinic acetylcholine) 5. G protein coupled receptors (GCPR)-receptor triggers activation of G protein which initiates cascade of downstream signalling which alters concentration of a second messenger eg IP3, cAMP RECEPTORS ARE TISSUE SPECIFIC – Angiotensin (a peptide hormone) will act on Angiotensin (AT) receptors located on vascular smooth muscle (but not other smooth muscle) – On kidney epithelium specifically proximal tubular epithelium as secreted in urine in tubular lumen Question Time Which statement on receptors is false? A-Receptors possess structural and steric specificity B-Receptors are expressed equally in all tissues C- Receptors are saturable and finite (limited number of binding sites) THE DOSE-RESPONSE RELATIONSHIP An Agonist is a drug which interacts with receptors; the resulting drug-receptor complex generates a response A dose response curve refers to the relationship between an effect of a drug and the amount of drug given. Heart Rate (BPM) Response Adrenaline Agonist DOSE-RESPONSE IS A GRADED RESPONSE The size of response varies with the proportion of receptors occupied by the agonist which varies with the concentration of the agonist. Dose Response Curves-Efficacy Katzung &Trevor- Basic and Clinical Pharmacology 11 th edition Analysis of Dose Response Curves enables the measurement of severa important parameters including Emax and EC50 which determine the efficacy and potency of the drug Emax is the maximum effect an agonist can produce regardless of dose (measure of Efficacy) EC50 is the effective concentration of drug required to produce 50% of maximal effect (measure of Potency)  Dose Response Curves-Potency Potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. Potency is related to ‘affinity’ of the receptor for the drug and number of receptors available Isoprenaline (A) 20 mM> Adrenaline (B) 80 mM> Noradrenaline (C) 300 mM Drug receptor interactions-Binding Drugs/agonists bind specifically to a receptor There are a limited number of receptors in any tissue (heart, blood vessel, muscle etc) Binding is saturable, i.e. at a certain concentration no more binding is possible Bmax and Kd can determined from binding curves Dose Binding Curve Bmax: Maximum number of receptors bound Kd: Concentration at which 50% of receptors are bound Kd : Dissociation constant-measure of affinity Binding studies Directly measure the binding of radiolabeled drug to tissue Can be used for agonist or antagonist Does not determine response Functional studies not binding studies determine response RADIOLABEL BINDING QUANTIFICATION OF DRUG ACTION Dose-response curves can be interpreted to measure drug affinity (Kd) and maximal effect (E max) Langmuir equation quantifies drug binding interaction Law of mass action applies. We assume that binding is reversible All receptors are equally accessible to ligands Receptors are free or bound to drug Binding does not alter receptor or ligand Hill Langmuir  DR  D  RT    D  K d  Emax E Langmuir: This equation states that the amount of drug bound to the receptor is dependent on the drug concentration and Kd. No of occupied receptors -focup = [DR]/[RT] can be calculated by summing up the different forms of the receptor in the system (free and occupied).Can also be calculated using Kd. Kd-concentration of free ligand at which 50% of receptor. sites are occupied (f=0.5) Law of mass action – not totally accurate! Receptors are free or bound to drug – Receptors can exist in desensitized state Binding does not alter receptor or ligand – Receptors change shape after binding ligand Binding is reversible – Binding can be irreversible  RECEPTOR DESENSITISATION/TACHYPHYLAXIS Frequent or continuous exposure to agonist can result in short term reduction of the receptor response (tachyphylaxis) Ending a signal is just as important as initiating a signal as it provides precise control – Receptor internalization can reduce receptors available to agonist eg Intracellular molecule such as B-Arrestin can block access of G proteins to activated receptor – Continuous activation can lead to depletion of downstream mediators Tolerance: similar, but develops more slowly  RECEPTOR DESENSITIZATION & INTERNALIZATION Phosphorylation of G protein coupled receptor kinases (GRKs) specifically prepares the activated receptor for Arrestin binding. B-Arrestin binding to the receptor blocks further G protein-mediated signalling and targets receptors for internalization. SPARE RECEPTORS When maximum drug response (Emax) is obtained at less than 100% occupancy of the receptors, spare receptors are thought to exist The no. of receptors exceeds the no. of effector molecules resulting in increased sensitivity to agonist In this system EC50 less than Kd (to achieve 50% max effect less than 50% of receptors must be activated) Question Time When spare receptors are present A. EC50 less than Kd B. EC50 equals Kd C. EC50 greater than Kd  Define the terms 'ligands' and 'receptors’ Describe the way in which receptors are defined (characteristics) Explain the concept of a dose-response relationships Explain quantitative concepts [Kd; Bmax; IC50/EC50] Define 'agonists'; 'partial agonists'; 'intrinsic activity’ Discuss the mechanism by which partial agonists work for the different receptor types  Agonists and Partial Agonists An agonist is a drug that activates its receptor upon binding elicit a full response (effect) A partial agonist binds to its receptor but produces a smaller effect (Emax) at full dosage then a full agonist An antagonist is a substance that binds to a receptor but does not activate and can block the activity of other agonists a=1: Full agonist 1>a>0: Partial agonist a=0: antagonist Partial agonist binds to all of the receptors a=intrinisic activity but the probability of an occupied receptor generating a response is less than that for the full agonist.  Agonists & Partial Agonists Intrinsic activity (a) is the ability to produce a response. Also called Efficacy Describes variability in agonist response The maximum response produced by a partial agonist is determined by its intrinsic activity Here, Drugs A & B have the same Efficacy. Drug A has greater Potency than Drug B. Although Drug C has lower efficacy than B, It is more potent than B at lower drug concentrations.  Partial Agonists Another key property of partial agonists is that they can display both agonistic and antagonistic effects A partial agonist can act as an antagonist, competing with the full agonist for the same receptor and thereby reducing the ability of the full agonist to produce its maximum effect EXAMPLES of PARTIAL AGONISTS Aripiprazole (Abilify ®) is a dopamine partial agonist used in the treatment of schizophrenia Schizophrenia-dysregulated dopamine activity (excess and deficit) Aripiprazole exerts agonist effects in areas of dopamine deficit, while exerting sufficient antagonist effects in areas of dopamine hyperactivity.  EXAMPLES of PARTIAL AGONISTS Buprenorphine (Suboxone ®) -opioid partial agonist Produces significant analgesic effects (pain relief) by stimulating opioid receptors, - Less effective then the full agonist morphine - but has a lower risk for producing life-threatening respiratory depression (side effect opiates)  SUMMARY CONCEPTS Log dose response curve Binding curve Efficacy (Emax) Max no of receptors bound (Bmax) Potency EC50. Kd – dissocitation constant. Langmuir: This equation states that the amount o drug bound to the receptor is dependent on the d concentration and Kd. EC50 is the effective concentration Kd is the concentration at of drug required to produce 50%which 50% of receptors are bound of maximal effect Spare Receptor Efficacy based on intrinsic activity Spare Receptors ability to produce a response Conc to produce 50% response (EC50) A partial agonist binds to its receptor but Is lower than conc at which 50% are bound produces a smaller effect (Emax) at full dosage Reason-spare receptors increase sensitivity of then a full agonist agonist-more drug receptor interactions possible Question Time Question 1 Which drugs is most potent on this graph? A, B or C? Question 2 Which drugs elicits a sub maximal response and could be a partial agonist?