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RECEPTORS AND RECEPTOR
SUPERFAMILIES
Dr.Rahul Kunkulol Asso. Professor dept. of Pharmacology
RMC,LONI
Receptor
DRUG
INTRODUCTION
“Corpora non agunt nisi fixate”.P. Ehrlich (1908)
Paul Ehrlich described drug-receptor binding:(“Agents do not act unless they are bound”)
Receptor
DRUG
DrugsDrugs can be defined as agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect.
Drugs can be
stimulatory or
inhibitory
Drugs
Drugs interact with biological systems in ways that mimic, resemble or otherwise affect the natural chemicals of the body.
• - or -Drugs can produce effects by virtue of :• Acidic or basic properties (e.g. Antacids,
protamine)• Surfactant properties (amphotericin)• Ability to denature proteins (astringents)• Osmotic properties (laxatives, diuretics)• Physicochemical interactions with membrane
lipids (general and local anesthetics).
DRUG SPECIFICITY Specificity is reciprocal: Individual classes of drug bind only to certain targets, and individual targets recognized only certain classes of drug.No drugs are completely specific in their action. In many cases increasing the dose of a drug will cause it affect target other than the principle one, and this can lead to side effects. E.g. TCA
Targets for drug action
•Receptor
•Ion channels
•Enzymes
•Carrier molecules
Four kinds of
regulatory protein involved
as primary
drug targets.
Targets for drug action
ION CHANNELSLigand gated ion channels –incorporate a receptor and open or close only when the receptor is occupied by an agonist. Ex.- Local anesthetics (direct) Voltage gated ion channels-drugs binds on accessory sites on the channel protein and affect channel gating.Ex.- dihydropyridines (indirect)
ENZYMESMany drugs target enzymes. Often the drug molecule is a substrate analogue that act as a competitive inhibitor of the enzyme ,either reversibly or irreversibly. Examples:- Enzymes Inhibitors Acetylcholinesterase Neostigmine Cyclooxygenase Aspirin
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 receptorDrugs, as well as hormones, neurotransmitter, autacoids and toxins can make possible the transfer of information to cells by interaction with specific receptive molecules called “receptors”.
Receptor
DRUG
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.
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 Receptors
IUPHAR (International Union of Pharmacological Science)Pharmacological
Mediator (i.e. Insulin, Norepinephrine, estrogen)
Biochemical and BiophysicalSecond 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
GABAA RECEPTOR
GABAA 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
SIGNAL TRANSDUCTION
CLASSES OF G-PROTEINS Gs Gi Gq Go
Amplification………..?
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
PHOSPHOLIPASE C
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.
SteroidReceptor
Confomational change
Dimer
Move to nucleus and bind to hormone – responsive elements
Increase RNA Polymerase activity
Production of specific m RNA
NUCLEAR RECEPTORS
RECEPTOR SUPERFAMILIES
RECEPTOR SUPERFAMILIES
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 InteractionsTheory 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.
Dose response curve…...
Agonism and Antagonism
Cont..AGONIST: Binding + ActivationAgonists 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
R+D=
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.
Antagonism-Competitive
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
↓ number of available receptors -- ↓ 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.