RECEPTORS AND RECEPTOR
Asso. Professor dept.
“Corpora non agunt nisi fixate”.
P. Ehrlich (1908)
Paul Ehrlich described drug-receptor binding:
do not act unless they are bound”)
Слайд 11CARRIER 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 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
Слайд 14DRUG RECEPTOR INTERACTION
Receptor mediated response
Occupation of receptor by a
drug molecule may or may not
result in activation of the receptor.
Слайд 15CONCEPT 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 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
Слайд 17Classification of Receptors
IUPHAR (International Union of Pharmacological Science)
Mediator (i.e. Insulin, Norepinephrine,
Biochemical and Biophysical
Second messenger system (i,.e. cAMP, PLC, PLA)
Molecular or Structural
Subunit composition (i.e. 5HT1A )
Tissue (i.e muscle vs ganglionic nAChRs)
Cellular (i.e. Membrane bound vs Intracellular)
Слайд 18 RECEPTOR SUPERFAMILIES
LIGAND- GATED ION CHANNELS
G-PROTEIN COUPLED RECEPTORS
KINASE LINKED RECEPTORS
Слайд 19Type- Ionotropic receptors
Examples-Fast neurotransmitters :
LIGAND GATED ION CHANNELS
Слайд 21GATING MECHANISM
Post synaptic membrane inotropic receptor (LGIC)
Increased permeability of ions
Слайд 22STRUCTURE OF ACH NICOTINIC RECEPTOR
GT: GABA transaminase
SSD: Succinic semialdehyde dehydrogenase
Слайд 26G – PROTEIN COUPLED RECEPTORS
Location: Cell membrane
Слайд 29CLASSES OF G-PROTEINS
Слайд 31BIDIRECTIONAL CONTROL OF A TARGET ENZYME BY G PROTEIN ISOMERS
Слайд 33Receptor Signaling Pathways
Adenylate Cyclase (AC)
Guadenylyl Cyclase (GC)
Phospholipase C (PLC)
Phospholipase A (PLA2)
DAG and IP3
NO and CO
Na+, Ca2+, K+, Cl-
Слайд 34 Adenylate Cyclase
Activation of PK
Enzymes involved in energy metabolism, cell division, cell differentiation,
ion channels, and contractile proteins in smooth muscles
Слайд 37ION 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
Слайд 39KINASE 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.
Слайд 40SIGNAL TRANSDUCTION
Dimerisation of receptor
Autophosporylation of tyrosine residue
Binding of intracellular
Слайд 43NUCLEAR 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.
Move to nucleus and bind to hormone –
Increase RNA Polymerase activity
Production of specific m RNA
Слайд 53DESENSITISATION & 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.
Loss or change in receptors
Exhaustion of mediators
↑ metabolic degradation
of drug from cell
Слайд 55Drug-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.
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.
Слайд 60Partial Agonists
Full agonists → max response
Full response @ ~20% occupancy
agonists → sub maximal response
100% occupancy → ~40% response
Слайд 61Comparison of Affinity & Efficacy of Ligands
Ligand Affinity Efficacy
Antagonist ++++ -
Partial agonist ++++ ++
Слайд 62TWO STATE MODEL
The receptor shows the two conformational stage resting (R)
and activated (R*) which exist in equilibrium.
Normally when no ligand is present, the equilibrium lies far to the left.
Слайд 63In the presence of ligand (A) equilibrium will depend on equilibrium
constant i.e. β/α.
For pure antagonist it is zero.
For agonist it is a finite value.
For drug X β/α is small – partial agonist
For drug Y β/α is large – agonist
Therefore constant β/α is measure of efficacy
Слайд 65DRUG ANTAGONISM
The effect of one drug is diminished or completely abolished
in the presence of another.
Antagonism by receptor block
Noncompetitive antagonism, i.e. block of receptor – effector linkage
Two substances combine in solution and effect of active drug
is lost, e.g. Dimercaprol bind to heavy metals
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.
Слайд 67REVERSIBLE COMPETITIVE ANTAGONISM
Antagonist binds receptor but does not activates it.
[agonist] restores tissue response to agonist
In the presence of antagonist, the agonist log concentration effect curve is sifted to the right without change in slope or maximum.
Слайд 69IRREVERSIBLE 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
Слайд 70IRREVERSIBLE COMPETITIVE ANTAGONISM
Слайд 71NONCOMPETITIVE 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.
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.