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RECEPTORS AND RECEPTORSUPERFAMILIES Dr.Rahul Kunkulol Asso. Professor dept. of PharmacologyRMC,LONI
INTRODUCTION “Corpora non agunt nisi fixate”. P. Ehrlich (1908) Paul Ehrlich described drug-receptor binding: (“Agents do not act unless they are bound”)
Targets for drug action
Targets for drug action
CARRIER MOLECULE The transport across cell membranes of ions and organic molecules generally requires a carrier protein . Ex. 1.Transport of glucose,a.a. into the cell. 2.Transport of ions, organic molecule into the tubule.
RECEPTOR Receptor are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body. Chemical messengers : Hormones Drugs Transmitters Other mediators
Drug and receptor
DRUG RECEPTOR INTERACTION Receptor mediated response Binding Activation Occupation of receptor by a drug molecule may or may not result in activation of the receptor.
CONCEPT OF RECEPTOR Some authors used it to mean any target molecule with which drug molecule has to combined in order to elicit the effect which can include any of the four subtypes. In Pharmacology it is best to reserve the term receptor for interaction of regulatory type where a small molecule (Ligand) may function as agonist or as an antagonist. In practice this limits use of term receptors that have physiological regulatory function
Drug-Receptor Interactions Drug-receptor interactions serve as signals to trigger a cascade of events. This cascade or signaling pathway, is a collection of many cellular responses which serve to amplify the signal and produce a final effect. Effectors are thus the molecules that translate the drug-receptor interaction into changes in cellular activity. ? ? ? + ? ? ? ? ? ? ? ??? ? EFFECT DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR INTERACTION COMPLEX SYSTEM STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE SIGNALLING PATHWAY
Classification of ReceptorsIUPHAR (International Union of Pharmacological Science) Pharmacological Mediator (i.e. Insulin, Norepinephrine, estrogen) Biochemical and Biophysical Second messenger system (i,.e. cAMP, PLC, PLA) Molecular or Structural Subunit composition (i.e. 5HT1A ) Anatomical Tissue (i.e muscle vs ganglionic nAChRs) Cellular (i.e. Membrane bound vs Intracellular)
RECEPTOR SUPERFAMILIES LIGAND- GATED ION CHANNELS G-PROTEIN COUPLED RECEPTORS KINASE LINKED RECEPTORS NUCLEAR RECEPTORS
Type- Ionotropic receptors Location-cell membrane Effector-ion channel Coupling-direct Examples-Fast neurotransmitters : Nicotinic Ach Glutamate GABAA, LIGAND GATED ION CHANNELS
LIGAND GATED ION CHANNELS
GATING MECHANISM Neurotransmitter Post synaptic membrane inotropic receptor (LGIC) Increased permeability of ions Depolarization Action potential
STRUCTURE OF ACH NICOTINIC RECEPTOR
GABA metabolites Succinic Semialdehyde GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase GT SSD Cl-
G – PROTEIN COUPLED RECEPTORS Type: Metabotropic Location: Cell membrane Coupling: G-protein Exampels- Muscarinic, Adrenergic, Opioid, Dopamine, 5HT,Peptides,Purines
CLASSES OF G-PROTEINS Gs Gi Gq Go Amplification………..?
BIDIRECTIONAL CONTROL OF A TARGET ENZYME BY G PROTEIN ISOMERS
Receptor Signaling Pathways Adenylate Cyclase (AC) Guadenylyl Cyclase (GC) Phospholipase C (PLC) Phospholipase A (PLA2) Nitric oxide Synthase Ions cAMP cGMP DAG and IP3 Arachidonic acid NO and CO Na+, Ca2+, K+, Cl- SECOND MESSENGER EFFECTOR
Adenylate Cyclase ATP cAMP Activation of PK Phosphorylation of cell proteins 5AMP Enzymes involved in energy metabolism, cell division, cell differentiation, ion channels, and contractile proteins in smooth muscles
REGULATION OF ENERGY BY CAMP
ION CHANNELLS AS TARGET FOR G- PROTEINS GPCR controls ion channels directly by mechanism that they do not involve second messengers like cAMP or IP3. Either alpha or beta and gamma subunits of G protein acts as second messenger Ex-m ACH receptor enhances K+ permeability
KINASE LINKED RECEPTORS Mediate the actions of wide variety of proteins mediators including growth factors, cytokines & hormones such as insulin. Receptor for various hormones (insulin) & growth factor incorporate tyrosine kinase activity in their intracellular domain. Cytokine receptors have intracellular domain that activates cytosolic kinases when the receptor is occupied.
SIGNAL TRANSDUCTION Receptor Ligand binding Dimerisation of receptor Autophosporylation of tyrosine residue Binding of intracellular proteins Gene transcription
NUCLEAR RECEPTORS Nuclear receptors regulate gene transcription. Nuclear receptor-a misnomer as they are located in the cytosol and migrate to nucleus when ligand is present. Examples: Steroid hormones, thyroid hormones retinoic acid and vit. D.
Steroid Receptor Confomational change Dimer Move to nucleus and bind to hormone – responsive elements Increase RNA Polymerase activity Production of specific m RNA
LIGAND GATED ION CHANNELS
G – PROTEIN – COUPLED RECEPTORS
KINASE LINKED RECEPTORS
DESENSITISATION & TACHYPHYLAXIS Definition: TACHYPHYLAXIS The effect of a drug gradually diminishes when it is given continuously or repeatedly, which often develops in the course of minutes. Tolerance is conventionally used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develop. The distinction is not sharp. Refractoriness is used to indicate loss of therapeutic efficacy. Drug resistance is used to indicate loss of effectiveness of antimicrobial or anti tumor drugs.
MECHANISMS Loss or change in receptors Exhaustion of mediators ? metabolic degradation Physiological adaptation Active extrusion of drug from cell
Drug-Receptor Interactions Theory and assumptions of drug-receptor interactions. Drug Receptor interaction follows simple Law mass-action relationships, The magnitude of the response is proportional to the fraction of total receptor sites occupied by drug molecules. Combination or binding to receptor causes some event which leads to a response. Response to a drug is graded or dose-dependent.
Agonism and Antagonism
Cont.. AGONIST: Binding + Activation Agonists facilitate receptor response ANTAGONIST: If a drug binds to the receptor without causing activation and thereby prevents the agonists from binding, is termed as Antagonist. Tendency of a drug to bind the receptor is governed by its affinity, where as tendency of it, ones bound, to activate the receptor is denoted by its efficacy. PARTIAL AGONISTS: Drugs with intermediate levels of efficacy, such that even if 100% of receptors are occupied the tissue response is sub maximal.
PARTIAL & FULL AGONIST
Partial Agonists Full agonists ? max response Full response @ ~20% occupancy Partial agonists ? sub maximal response 100% occupancy ? ~40% response
Comparison of Affinity & Efficacy of Ligands Ligand Affinity Efficacy Agonist ++++ ++++ Antagonist ++++ - Partial agonist ++++ ++
TWO STATE MODEL The receptor shows the two conformational stage resting (R) and activated (R*) which exist in equilibrium. R R* Normally when no ligand is present, the equilibrium lies far to the left.
In the presence of ligand (A) equilibrium will depend on equilibrium constant i.e. ?/?. For pure antagonist it is zero. For agonist it is a finite value. For drug X ?/? is small – partial agonist For drug Y ?/? is large – agonist Therefore constant ?/? is measure of efficacy
DRUG ANTAGONISM The effect of one drug is diminished or completely abolished in the presence of another. CLASSIFICATION Chemical antagonism Pharmacokinetic antagonism Antagonism by receptor block Noncompetitive antagonism, i.e. block of receptor – effector linkage Physiological antagonism
Cont… CHEMICAL ANTAGONISM Two substances combine in solution and effect of active drug is lost, e.g. Dimercaprol bind to heavy metals PHARMACOKINETIC ANTAGONISM In this antagonist effectively reduces the concentration of the active drug at its site of action. This can happen various ways by increased metabolic degradation, decreased absorption or increased excretion.
REVERSIBLE COMPETITIVE ANTAGONISM Antagonist binds receptor but does not activates it. Incr’d [agonist] restores tissue response to agonist Antagonism “surmountable In the presence of antagonist, the agonist log concentration effect curve is sifted to the right without change in slope or maximum.
IRREVERSIBLE COMPETITIVE ANTAGONISM In this antagonist dissociates very slowly or not at all resulting in no change in antagonist occupancy when agonist is applied. Covalently bind receptors Irreversible, insurmountable antagonism v number of available receptors -- v agonist max response
IRREVERSIBLE COMPETITIVE ANTAGONISM
NONCOMPETITIVE ANTAGONISM Antagonists blocks at some points chain of events that lead to production of response by agonist. Effect will be slope and maximum of the agonist log concentration response curve. PHYSIOLOGICAL ANTAGONISM In this there is interaction of two drugs whose opposing action in the body tend to cancel each other example – Histamine and Omeprazole on parietal cell of gastric mucosa.