DOCSLIB.ORG

PHARMACODYNAMICS Receptor Pharmacology

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PHARMACODYNAMICS Receptor Pharmacology PHARMACODYNAMICS Receptor Pharmacology MAJID SHEYKHZADE & DARRYL S. PICKERING 10th Edition DEPT. OF DRUG DESIGN & PHARMACOLOGY FACULTY OF HEALTH & MEDICAL SCIENCES UNIVERSITY OF COPENHAGEN 2016 Preface These notes in pharmacodynamics and receptor pharmacology are originally based on reference 1 and have since been updated with the latest and the most important basic concepts in this field. These notes are intended as a supplementary text on pharmacodynamics and receptor pharmacology but further reading has been provided for those who want to follow up on topics. (See the literature sources below). These notes are prepared for undergraduate students in their final year of study for the Master of Science degree. The following literature sources are the bases for these notes and for further reading: 1- ”Almen Farmakologi” (Per Juul), 1984 2- ”Pharmacology” (H.P. Rang, M.M. Dale, J.M. Ritter, R.J. Flower, and G. Henderson) 8th Edition, 2016. ISBN: 978-0-7020-5362-7 3- ”Pharmacology Condensed” (M.M. Dale and D.G. Haylett), 2nd edition, 2009. 4- ”Pharmacologic Analysis of Drug-receptor interaction” (Terry Kenakin), 3rd edition, 1997. 5- ”Textbook of Receptor Pharmacology” (Edited by John C. Foreman, Torben Johansen and Alasdair J. Gibb), 3rd edition, 2011. ISBN: 978-1-4200-5254-1 6- ”A Pharmacology Primer” (Terry P. Kenakin), Theory, Applications, and Methods, third edition, 2009. ISBN: 978-0-12-374585-9 ii Table of Contents PHARMACODYNAMICS 1 DRUG-RECEPTOR INTERACTIONS 1 CONCENTRATION-RESPONSE RELATIONSHIPS 6 Classical occupation theory 6 Graphic representations of concentration-response relationships 11 Unexpected deviations from theory 13 The modified occupation theory 14 INTERACTIONS AT THE RECEPTOR LEVEL 17 Reversible-competitive antagonism 17 Non-competitive antagonism 17 Reversible-competitive antagonism: mathematical models 19 Irreversible-competitive antagonism 23 Partial agonism 25 iii PHARMACODYNAMICS Pharmacodynamics concerns the effects and mechanism(s) of action of drugs on the intact organism, individual organ as well as at the cellular, sub-cellular and molecular levels. Whereas the effects of a majority of drugs are known, in contrast, the mechanism of action for numerous drugs is only partially understood. While medical-pharmacological research for a number of years completely focused on kinetics (because of advanced developments in analytical chemistry techniques), in the last 20-30 years research has produced increased insights into the mechanisms of action of drugs at the molecular level. That has made feasible a more rational pharmacotherapy, a more rational development of new drugs and an increased insight into the pathophysiology and pathobiochemisty of disease. DRUG-RECEPTOR INTERACTIONS Receptors are sensitive macromolecules that carry out a central part of a chemical communications system which has the task of regulating and coordinating the function of all cells in an organism. Many drugs exert their effects through affecting biological receptors, i.e. the prerequisite for an effect is a binding to a receptor. This binding can, in its simplest form, be described via Langmuir’s adsorption isotherm, which builds upon the law of mass action. The binding kinetics described below presume a reversible, bimolecular process, where only a small portion of the drug molecules are bound to the receptors and where all receptor molecules are identical. This model can seemingly explain a series of drug-receptor relationships and it is reasonably simple to understand. Even though it certainly doesn’t represent the whole truth, with individual modifications it will be used as in the following notes. Drug Drug-Receptor Complex Ligand-binding domain k 1 Effector domain k k-1 Receptor Effect Figure 1 Drug-receptor interaction following the law of mass action. 1 In its simplest form the drug-receptor interaction (Figure 1) can be described by: k+1 A + R ⇔ AR k-1 where: A = drug, [A] = concentration of drug (units of M), R = receptor, [R] = concentration of free receptor (i.e. unbound receptor), [R]t = total receptor concentration, AR = drug-receptor complex, [AR] = concentration of drug-receptor complex, k+1 = association rate constant (units -1 -1 -1 of M s ), k-1 = dissociation rate constant (units of s ), KA = equilibrium dissociation constant -1 (also sometimes designated Kd) (units of M) and the affinity is the reciprocal of KA (M ). The rate of production (Vassoc.) of the drug-receptor complex is: Vassoc. = k+1 [A][R] (1) and the rate of dissociation (Vdissoc.) is: Vdissoc. = k−1 [AR] (2) In the equilibrium situation, where the association rate is equal to the dissociation rate, (i.e. Vassoc. = Vdissoc.), according to the law of mass action: [A] [R] k−1 1 = = KA = (3) [AR] k+1 Affinity where KA is the equilibrium dissociation constant. The reaction rate for drug-receptor complex production is: d[AR] = k [A] [R] - k [AR] (4) dt +1 −1 We know additionally that: [R]t = [AR] + [R] ⇒ [R] = [R]t – [AR]. The expression can therefore be rearranged to: d[AR] = k [A] ([R ] - [AR]) - k [AR] dt +1 t −1 d[AR] = k [A] [R ] - (k [A] + k ) [AR] (5) dt +1 t +1 −1 2 The above expression is a linear differential equation of first order. Solving for [AR] gives: [A] [R ] [AR] = t (1 - e- (k+1 [A] + k−1 ) t ) (6) KA + [A] Figure 2 The production of the drug-receptor complex (reference nr. 5). From equation (6) it appears that [AR] climbs exponentially with time until a constant level is attained at equilibrium (see Figure 2): [A] [R ] [AR] = t (7) KA + [A] The speed at which this equilibrium level is attained is given by (k+1[A] + k-1), which is dependent upon the rate constants k+1 and k-1 for, respectively, the association and dissociation as well as the drug concentration. KA is of special interest. This equilibrium constant gives the concentration of drug which occupies half of the receptors at equilibrium. Equation (7) is identical with the Michaelis-Menten equation, which describes the rate of enzymatic reactions. Dividing by [R]t on both sides of equation (7): [AR] [A] = (8) [R ]t KA + [A] 3 t -pKA KA KA [AR] / [R] [A] log [A] Figure 3 A: The relation between drug concentration [A] and the fraction of drug-occupied receptors [AR]/[R]t. B: Same relation, but with a logarithmic x-axis (Reference nr. 4). With [A] as x-axis and the fraction of receptors which are occupied by drug as the y-axis, the drug-receptor binding graph will be hyperbolic on a linear axis scale (going through zero). A semi-logarithmic graph with log [A] as the x-axis (and the same linear y-axis) produces a symmetric S-form curve (Figure 3). KA, the equilibrium dissociation constant can, amongst other things, be determined by means of in vitro receptor binding studies (saturation experiments), where the tissue containing the receptors in question is incubated with increasing concentrations of a radioactively labeled drug. By relating the amount of bound drug (fmol/g tissue) as a function of the drug concentration (the free, or non-bound, concentration; nmol/L) the concentration giving half-maximal binding (KA) can be determined. Sometimes, -log(KA) (or pKA) is used as a measure of affinity (the larger pKA, the larger the affinity). ‘BLACK BOX’ Initial Drug Receptor AMPLIFICATION Effector Effect Stimulus Figure 4 Schematic representation of possible amplification steps between drug-receptor binding and effect (Reference nr. 1). As for the link between binding and effect, we know only very little about the intracellular processes which are activated by stimulation of a receptor. This has led to introduction of the concept of the ‘black box’ (Figure 4) which is a collective term for all the processes that one cannot immediately measure. 4 It is only now, after many years of intensive research in intracellular reactions, that we are starting to have some insight about what happens after production of the drug-receptor complex. We now know that a stimulation of the receptor leads to a sequence of events which result in an amplification of the signal. An example of such a possible chain reaction is indicated in Figure 5, showing adrenalin’s affect upon adenylate cyclase (a membrane bound enzyme) with production of cAMP (cyclic adenosine monophosphate, a so-called “second messenger”) followed by a series of processes which result in cellular responses (e.g. glycogenolysis and energy generation). Figure 5 The sequence of enzymatic reactions from adrenalin’s stimulation of adenylate cyclase to the resulting effect (Reference nr. 3). 5 CONCENTRATION-RESPONSE RELATIONSHIPS Classical occupation theory is built upon two main assumptions: 1. The magnitude of the measured effect is proportional to the fraction of drug-occupied receptors, i.e. there is a linear relationship between the fraction of drug-occupied receptors and effect: E = α [AR] (9) 2. The maximal effect is obtained when all receptors are occupied with drug: Emax = α [R]t (10) If equations (9) and (10) are combined: E α [AR] [AR] = = (11) Emax α [R ]t [R ]t If equation (11) is combined with equation (8), the following relation between effect and drug concentration is obtained: E [A] = (12) Emax KA + [A] E⋅ [A] = E = max Multiply both sides by Emax: (13) KA + [A] It is apparent that here also is found an application of the Michaelis-Menten relation by a description of the concentration-response relation as in the case of enzymatic reactions. Emax (the maximal effect which can be obtained with the drug concerned) corresponds to the enzyme kinetic’s Vmax (the maximal velocity which can be obtained by the reaction). KA (equilibrium dissociation constant) corresponds to the enzyme kinetic’s Michaelis-constant (Km). Emax can be expressed in absolute units, but most often is stated as a relative percentage or fraction (i.e.
Load more

Recommended publications
  • Principle of Pharmacodynamics
    Principle of pharmacodynamics Dr. M. Emamghoreishi Full Professor Department of Pharmacology Medical School Shiraz University of Medical Sciences Email:[email protected] Reference: Basic & Clinical Pharmacology: Bertrum G. Katzung and Anthony J. Treveror, 13th edition, 2015, chapter 20, p. 336-351 Learning Objectives: At the end of sessions, students should be able to: 1. Define pharmacology and explain its importance for a clinician. 2. Define ―drug receptor‖. 3. Explain the nature of drug receptors. 4. Describe other sites of drug actions. 5. Explain the drug-receptor interaction. 6. Define the terms ―affinity‖, ―intrinsic activity‖ and ―Kd‖. 7. Explain the terms ―agonist‖ and ―antagonist‖ and their different types. 8. Explain chemical and physiological antagonists. 9. Explain the differences in drug responsiveness. 10. Explain tolerance, tachyphylaxis, and overshoot. 11. Define different dose-response curves. 12. Explain the information that can be obtained from a graded dose-response curve. 13. Describe the potency and efficacy of drugs. 14. Explain shift of dose-response curves in the presence of competitive and irreversible antagonists and its importance in clinical application of antagonists. 15. Explain the information that can be obtained from a quantal dose-response curve. 16. Define the terms ED50, TD50, LD50, therapeutic index and certain safety factor. What is Pharmacology?It is defined as the study of drugs (substances used to prevent, diagnose, and treat disease). Pharmacology is the science that deals with the interactions betweena drug and the bodyor living systems. The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamicprocesses.These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease.
    [Show full text]
  • Opioid Receptorsreceptors
    OPIOIDOPIOID RECEPTORSRECEPTORS defined or “classical” types of opioid receptor µ,dk and . Alistair Corbett, Sandy McKnight and Graeme Genes encoding for these receptors have been cloned.5, Henderson 6,7,8 More recently, cDNA encoding an “orphan” receptor Dr Alistair Corbett is Lecturer in the School of was identified which has a high degree of homology to Biological and Biomedical Sciences, Glasgow the “classical” opioid receptors; on structural grounds Caledonian University, Cowcaddens Road, this receptor is an opioid receptor and has been named Glasgow G4 0BA, UK. ORL (opioid receptor-like).9 As would be predicted from 1 Dr Sandy McKnight is Associate Director, Parke- their known abilities to couple through pertussis toxin- Davis Neuroscience Research Centre, sensitive G-proteins, all of the cloned opioid receptors Cambridge University Forvie Site, Robinson possess the same general structure of an extracellular Way, Cambridge CB2 2QB, UK. N-terminal region, seven transmembrane domains and Professor Graeme Henderson is Professor of intracellular C-terminal tail structure. There is Pharmacology and Head of Department, pharmacological evidence for subtypes of each Department of Pharmacology, School of Medical receptor and other types of novel, less well- Sciences, University of Bristol, University Walk, characterised opioid receptors,eliz , , , , have also been Bristol BS8 1TD, UK. postulated. Thes -receptor, however, is no longer regarded as an opioid receptor. Introduction Receptor Subtypes Preparations of the opium poppy papaver somniferum m-Receptor subtypes have been used for many hundreds of years to relieve The MOR-1 gene, encoding for one form of them - pain. In 1803, Sertürner isolated a crystalline sample of receptor, shows approximately 50-70% homology to the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the the genes encoding for thedk -(DOR-1), -(KOR-1) and orphan (ORL ) receptors.
    [Show full text]
  • Pharmacodynamics Drug Receptor Interactions Part-2
    Pharmacodynamics: (Drug Receptor Interactions, Part 2) ………………………………………………………………………………………………………………………………………………………………………………………………………………… VPT: Unit I; Lecture-22 (Dated 03.12.2020) Dr. Nirbhay Kumar Asstt. Professor & Head Deptt. of Veterinary Pharmacology & Toxicology Bihar Veterinary College, Bihar Animal Sciences University, Patna Drug Receptor Interactions Agonist It is a drug that possesses affinity for a particular receptor and causes a change in the receptor that result in an observable effect. Full agonist: Produces a maximal response by occupying all or a fraction of receptors. (Affinity=1, Efficacy=1) Partial agonist: Produces less than a maximal response even when the drug occupies all of the receptors. (Affinity=1, Efficacy= 0 to 1) Inverse agonist: Activates a receptor to produce an effect in the opposite direction to that of the well recognized agonist. (Affinity=1, Efficacy= –1 to 0). Source: Rang & Dale’s Pharmacology, Elsevier Source: Good & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edn. Antagonist An antagonist is a drug that blocks the response produced by an agonist. Antagonists interact with the receptor or other components of the effector mechanism, but antagonists are devoid of intrinsic activity (Affinity=1, Efficacy=0). Antagonist contd… Competitive Antagonism: It is completely reversible; an increase in the concentration of the agonist in the bio-phase will overcome the effect of the antagonist. Example: Atropine (Antimuscarinic agent) Diphenhydramine (H1 receptor blocker) Non-competitive antagonism: The agonist has no influence upon the degree of antagonism or its reversibility. Example: Platelet inhibiting action of aspirin (The thromboxane synthase enzyme of platelets is irreversibly inhibited by aspirin, a process that is reversed only by production of new platelets).
    [Show full text]
  • Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity Kelly A
    International Journal of Neuropsychopharmacology (2018) 21(10): 962–977 doi:10.1093/ijnp/pyy071 Advance Access Publication: August 6, 2018 Review review Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity Kelly A. Berg and William P. Clarke Department of Pharmacology, University of Texas Health, San Antonio, Texas. Correspondence: William P. Clarke, PhD, Department of Pharmacology, Mail Stop 7764, UT Health at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 ([email protected]). Abstract Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured.
    [Show full text]
  • Biopharmacy Practice
    University of Szeged Biopharmacy practice Editor: Árpád Márki, Ph.D. Authors: Árpád Márki, Ph.D. Adrienn Seres, Ph.D. Anita Sztojkov-Ivanov, Ph.D. Reviewed by: Szilárd Pál, Ph.D. Szeged, 2015. This work is supported by the European Union, co-financed by the European Social Fund, within the framework of "Coordinated, practice-oriented, student-friendly modernization of biomedical education in three Hungarian universities (Pécs, Debrecen, Szeged), with focus on the strengthening of international competitiveness" TÁMOP-4.1.1.C-13/1/KONV-2014-0001 project. The curriculum cannot be sold in any form! Contents Contents ...................................................................................................................................... 2 1. Definitions, routes of drug administration ............................................................................. 6 1.1. Definitions ....................................................................................................................... 6 1.2. Routes of drug administration ......................................................................................... 7 1.3. Questions ....................................................................................................................... 10 2. Receptors .............................................................................................................................. 11 2.1. Definitions ....................................................................................................................
    [Show full text]
  • Measuring Ligand Efficacy at the Mu- Opioid Receptor Using A
    RESEARCH ARTICLE Measuring ligand efficacy at the mu- opioid receptor using a conformational biosensor Kathryn E Livingston1,2, Jacob P Mahoney1,2, Aashish Manglik3, Roger K Sunahara4, John R Traynor1,2* 1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States; 2Edward F Domino Research Center, University of Michigan, Ann Arbor, United States; 3Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, United States; 4Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, United States Abstract The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (m-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to m- OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of m-OR. We further show that positive allosteric modulators of m-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell- free, signal transduction-independent and is generally applicable to GPCRs. DOI: https://doi.org/10.7554/eLife.32499.001 *For correspondence: [email protected] Competing interests: The authors declare that no Introduction competing interests exist.
    [Show full text]
  • When Simple Agonism Is Not Enough: Emerging Modalities of GPCR Ligands Nicola J
    When simple agonism is not enough: emerging modalities of GPCR ligands Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan To cite this version: Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan. When simple agonism is not enough: emerging modalities of GPCR ligands. Molecular and Cellular Endocrinology, Elsevier, 2010, 331 (2), pp.241. 10.1016/j.mce.2010.07.009. hal-00654484 HAL Id: hal-00654484 https://hal.archives-ouvertes.fr/hal-00654484 Submitted on 22 Dec 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: When simple agonism is not enough: emerging modalities of GPCR ligands Authors: Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan PII: S0303-7207(10)00370-9 DOI: doi:10.1016/j.mce.2010.07.009 Reference: MCE 7596 To appear in: Molecular and Cellular Endocrinology Received date: 15-1-2010 Revised date: 15-6-2010 Accepted date: 13-7-2010 Please cite this article as: Smith, N.J., Bennett, K.A., Milligan, G., When simple agonism is not enough: emerging modalities of GPCR ligands, Molecular and Cellular Endocrinology (2010), doi:10.1016/j.mce.2010.07.009 This is a PDF file of an unedited manuscript that has been accepted for publication.
    [Show full text]
  • The Importance of Serotonergic and Adrenergic Receptors for the Induction and Expression of One-Trial Cocaine-Induced Behavioral Sensitization" (2016)
    California State University, San Bernardino CSUSB ScholarWorks Electronic Theses, Projects, and Dissertations Office of aduateGr Studies 12-2016 THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE- TRIAL COCAINE-INDUCED BEHAVIORAL SENSITIZATION Krista N. Rudberg California State University - San Bernardino Follow this and additional works at: https://scholarworks.lib.csusb.edu/etd Part of the Biological Psychology Commons, and the Pharmacology Commons Recommended Citation Rudberg, Krista N., "THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE-TRIAL COCAINE-INDUCED BEHAVIORAL SENSITIZATION" (2016). Electronic Theses, Projects, and Dissertations. 420. https://scholarworks.lib.csusb.edu/etd/420 This Thesis is brought to you for free and open access by the Office of aduateGr Studies at CSUSB ScholarWorks. It has been accepted for inclusion in Electronic Theses, Projects, and Dissertations by an authorized administrator of CSUSB ScholarWorks. For more information, please contact [email protected]. THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE-TRIAL COCAINE- INDUCED BEHAVIORAL SENSITIZATION A Thesis Presented to the Faculty of California State University, San Bernardino In Partial Fulfillment of the Requirements for the Degree Master of Arts in General/Experimental Psychology by Krista Nicole Rudberg December 2016 THE IMPORTANCE OF SEROTONERGIC AND ADRENERGIC RECEPTORS FOR THE INDUCTION AND EXPRESSION OF ONE-TRIAL COCAINE- INDUCED BEHAVIORAL SENSITIZATION A Thesis Presented to the Faculty of California State University, San Bernardino by Krista Nicole Rudberg December 2016 Approved by: Sanders McDougall, Committee Chair, Psychology Cynthia Crawford, Committee Member Matthew Riggs, Committee Member © 2016 Krista Nicole Rudberg ABSTRACT Addiction is a complex process in which behavioral sensitization may be an important component.
    [Show full text]
  • Drug Action-Receptor Theory
    Drug action-Receptor Theory Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. The binding can be specific and reversible. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes. Few if any drugs are absolutely specific for one receptor or subtype, but most have relative selectivity. Selectivity is the degree to which a drug acts on a given site relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors. A drug’s ability to affect a given receptor is related to the drug’s affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response). A drug’s affinity and activity are determined by its chemical structure. The pharmacologic effect is also determined by the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that control the rate of drug association and dissociation from the target. A longer residence time explains a prolonged pharmacologic effect. Drugs with long residence times include finasteride and darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes toxicity. Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory mechanisms.
    [Show full text]
  • Response Vs. Log [L] - Full Agonist
    DavidsonX – D001x – Medicinal Chemistry Chapter 5 – Receptors Part 2 – Ligands Video Clip – Ligand Types Ligands can have different effects on a receptor. Each type of ligand can be readily classified according to its behavior. A type of ligand is the full agonist. The term agonist refers to a compound that binds a receptor and elicits a response (E). Full agonists elicit the same level of full response (E = Emax = 100%) as the endogenous ligand of the receptor. Graphically, a receptor-ligand interaction is plotted as response (E/Emax) vs. log [L]. The relationship is sigmoidal. A full agonist approaches full response (E/Emax = 1.0) as log [L] reaches relatively high levels. response vs. log [L] - full agonist 1 0.9 0.8 0.7 x a 0.6 m E 0.5 / E 0.4 0.3 0.2 0.1 0 log [L] Two ligands can achieve a full response without being equivalent. Ligands can differ with respect to the concentration required to trigger a response. A ligand that affects a response at a lower concentration has a higher potency. Potencies are measured as the effective ligand concentration required to reach a 50% response – EC50 or, in these graphs, log [EC50]. A more potent ligand has a lower EC50 value. full agonist comparison 1 0.9 full agonist 1 0.8 (more potent) full agonist 2 0.7 (less potent) x a 0.6 log EC m 50 E 0.5 / E 0.4 0.3 log EC 0.2 50 0.1 0 log [L] Partial agonists also cause a response, but they cannot reach the same, 100% response level of the endogenous ligand.
    [Show full text]
  • A1-Blocker Therapy in the Nineties: Focus on the Disease
    Prostate Cancer and Prostatic Diseases (1999) 2 Suppl 4, S9±S15 ß 1999 Stockton Press All rights reserved 1365±7852/99 $15.00 http://www.stockton-press.co.uk/pcan a1-Blocker therapy in the nineties: focus on the disease KHoÈfner1* 1Department of Urology, Hannover Medical School, Hannover, Germany Therapy for benign prostatic hyperplasia has evolved rapidly over the last decade, with the introduction in the early 1990s of new agents such as a1-blockers and 5a-reductase inhibitors. The major advantage of a1-blockers over 5a- reductase inhibitors is their rapid onset of action. Maximum ¯ow rate is improved after ®rst administration and optimal symptom relief is usually reached within 2 ± 3 months. In addition, a1-blockers are effective regardless of prostate size and they provide a similar degree of symptom relief in patients with or without bladder outlet obstruction. The main adverse events with the a1- blockers relate to their effects on the cardiovascular system (postural hypoten- sion) and central penetration (asthenia, somnolence). Newer uroselective a1- blockers, such as alfuzosin and tamsulosin, have a better safety pro®le and, as such, do not require initial dose titration. Alfuzosin has also been shown in a six- month study to signi®cantly reduce both residual urine and the incidence of acute urinary retention (AUR) compared with placebo. In addition, alfuzosin is effective in improving the success rate of a trial without catheter in patients with AUR. Keywords: benign prostatic hyperplasia; prostate; a1-blockers; 5a-reductase inhibitors; acute urinary retention; LUTS Management of BPH adrenoceptors. Medical management of BPH suddenly exploded at the beginning of the 1990s with the introduc- Therapy for benign prostatic hyperplasia (BPH) has tion of selective a1-blockers and 5a-reductase inhibitors.
    [Show full text]
  • Biased Receptor Functionality Versus Biased Agonism in G-Protein-Coupled Receptors Journal Xyz 2017; 1 (2): 122–135
    BioMol Concepts 2018; 9: 143–154 Review Open Access Rafael Franco*, David Aguinaga, Jasmina Jiménez, Jaume Lillo, Eva Martínez-Pinilla*#, Gemma Navarro# Biased receptor functionality versus biased agonism in G-protein-coupled receptors Journal xyz 2017; 1 (2): 122–135 https://doi.org/10.1515/bmc-2018-0013 b-arrestins or calcium sensors are also provided. Each of receivedThe FirstJuly 19, Decade 2018; accepted (1964-1972) November 2, 2018. the functional GPCR units (which are finite in number) has Abstract:Research Functional Article selectivity is a property of G-protein- a specific conformation. Binding of agonist to a specific coupled receptors (GPCRs) by which activation by conformation, i.e. GPCR activation, is sensitive to the differentMax Musterman, agonists leads Paul to differentPlaceholder signal transduction kinetics of the agonist-receptor interactions. All these mechanisms. This phenomenon is also known as biased players are involved in the contrasting outputs obtained agonismWhat and Is has So attracted Different the interest Aboutof drug discovery when different agonists are assayed. programsNeuroenhancement? in both academy and industry. This relatively recent concept has raised concerns as to the validity and Keywords: conformational landscape; GPCR heteromer; realWas translational ist so value anders of the results am showing Neuroenhancement? bias; firstly cytocrin; effectors; dimer; oligomer; structure. biased agonism may vary significantly depending on the cellPharmacological type and the experimental and Mental constraints,
    [Show full text]