Download Types of receptors

Receptor classification, properties and types.
Learning objectives
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Describe the two primary properties of a drug,and how a receptor differs
from an inert binding site.
Define the following drug properties,agonist,antagonist,partial
agonist,affinity,efficacy,potency.
Descibe the typical dose response curve for a drug and label the positions
on the curve that are used to define drug potency and efficacy.
Explain the difference between selectivity and specificity of drug effect,and
which is more commonly observed,
Explain what is meant by additive,potentiative and synergistic drug effects.
Nature of receptors
Majority of receptors are protein in nature, a receptor may be:
An enzymatic protein:
Dihydrofolatereductase e.g. TRIMETHOPRIM
Monoamine oxidase e.g. PHENELZINE AND ISOCARBOXAZID
Xanthine oxidasee.g ALLOPURINOL
Types of receptors
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Regulatory – change the activity of cellular enzymes
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Enzymes – may be inhibited or activated
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Transport – e.g. Na+ /K+ATP’ase
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Structural – these form cell parts
Examples of receptors
Structural protein:
Tubulin = colchicin
Transport protein:
Na – K ATPaseDIGITALIS
H – K ATPaseOMEPRAZOLE
Ionic channel:
Calcium channels = Ca++ blockers
Sodium channels = anesthetics
Regulatory protein:
Mediating the effects of neurotransmitters, hormones and autacoids
Nucleic acids (RNA & DNA):
For antiviral and anticancer drugs
Receptors are situated on surface of cell or inside cell (cytoplasm
and nucleus).
D+R
DR Complex
Affinity
Affinity – measure of propensity of a drug to bind receptor; the
attractiveness of drug and receptor
 Covalent bonds are stable and
essentially irreversible
 Electrostatic bonds may be strong
or weak, but are usually
reversible
AFFINITY
Ability of a drug to bind a receptor is called
“AFFINITY” of the drug for receptor.
INTRINSIC ACTIVITY
Ability of drug to produce pharmacological effect after binding to a receptor
is called “INTRINSIC ACTIVITY”
Selective binding of a drug to a receptor is specific and implies high degree
of complimentarily in their chemical structure.
Agonist
A drug having high affinity for receptor and has high
intrinsic activity is called “AGONIST”
OR
A drug that initiates a pharmacological action by binding to a receptor
thatmimics the action of endogenous compounds is called “AGONIST”
Types of Agonist Drugs
Two types
Full – an agonist with maximal efficacy
Partial – an agonist with less then maximal
efficacy
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High affinity
High intrinsic activity
Agonist
Agonist
PARTIAL AGONIST
A drug having same affinity for receptor as an agonist
but less intrinsic activity than full agonist is called
“PARTIAL AGONIST”.
A partial agonist in presence of full agonist acts as
antagonist, as it occupies the receptor and does not
allow the full agonist to bind with receptor.
Agonists and antagonists
 agonist has affinity plus intrinsic activity
 antagonist has affinity but no intrinsic activity
 partial agonist has affinity and less intrinsic activity
 competitive antagonists can be overcome
REVERSE OR INVERSE AGONIST
Some drugs produce pharmacological responses by binding to the receptors that
are specifically opposite to those of an agonist, such drugs are called “REVERSE
OR INVERSE AGONIST.”
For example agonist action of benzodiazepines on benzodiazepine receptor in
C.N.S produces sedation, muscle relaxation, anxiolysis and controls convulsions.
-carolines also bind to these receptors and cause stimulation, anxiety, increased
muscle tone and convulsions.
Both benzodiazepines and -carolines act as agonist and produce opposing effects,
in this example benzodiazepines act as reverse agonist.
Antagonist
A drug having high affinity for receptor but has poor or no intrinsic activity is
called “ANTAGONIST”.
OR
A drug that bind with receptor but does not initiate action (interfere with
binding of agonist) is called “ANTAGONIST”.
• High affinity
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Antagonist Drug
Antagonists interact with the receptor but do NOT
change the receptor
They have affinity but NO intrinsic activity
TYPES
Competitive
Noncompetitive
Competitive Antagonist
Competes with agonist for receptor
Surmountable with increasing agonist concentration
Displaces agonist dose response curve to the right (dextral shift)
Reduces the apparent affinity of the agonist
Low intrinsic
activity
Antagonist
Reversible Antagonist
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High affinity
Low intrinsic activity
• High affinity
Antagonist
• Low intrinsic activity
Irreversible Antagonist
Irreversible Antagonist
Noncompetitive Antagonist
Drug binds to receptor and stays bound
Irreversible – does not let go of receptor
Produces slight dextral shift in the agonist DR curve in the low concentration range
This looks like competitive antagonist but, as more and more receptors are bound (and
essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect
Receptor properties
A drug may act on more than one type of receptors differing both in function and binding
characteristics.
Drug receptors are dynamic not static.
Number of receptors is not fixed but is constantly being changed.
When number of receptors is increased it is called “Up Regulation” and when number of
receptors is decreased it is called “Down Regulation.”
Change in the number of receptors depends upon
Disease State
Quantity
Frequency and duration of the drug used
Persistent use of antagonist causes up regulation of receptors and that of agonist
causes down regulation of receptors
Receptor Regulation
Sensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker
2. Inhibition of synthesis or release of hormone/neurotransmitter
Denervation
Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist
Desensitization
 Agonists tend to desensitize receptors
 Homologous (decreased receptor number)
 Heterologous (decreased signal transduction)
 Antagonists tend to up regulate receptors
Signaling Mechanisms
 Binding of an agonist drug to its receptor activates an effector or
signaling mechanism.
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 Several different types of drug responsive signaling mechanisms are
known.
Intracellular receptors
 These include receptors for steroids, thyroxine, gonadal steroids and
vitamin D.
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• Binding of drugs or hormones to such receptors cause dimerization of
hormone receptor complex.
• Such complexes translocate to the nucleus, where they interact with
response elements in spacer DNA.
• This leads to changes in gene expression.
• Pharmacologic responses elicited via modification of gene expression are
slower in onset but longer in duration.
• Membrane receptors directly coupled to ion channels
• Drugs bind to receptors on membrane and regulate flow of ions through
them.
• Do not require secondary messengers i.e. directly coupled to ion channels.
• Examples
• Acetylcholine in neuromuscular junction coupled to Na ion channels
• GABA receptors coupled to Cl ion channels
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• Receptors linked via G- proteins
• Many receptors are coupled via GTP binding proteins (G-proteins) to
adenylyl cyclase, the enzyme that converts ATP to cAMP, a second
messenger that promotes protein phosphorylation by activating protein
kinase A.
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• These receptors are typically serpentine with 7 transmembrane spanning
domains
• Gs Proteins
• Binding of agonists to receptors linked to Gs proteins increases cAMP
production.
• Examples include catecholamine (beta receptors), glucagon receptors,
histamine (H2) etc.
• Gi Proteins
• Binding of agonists to receptors linked to Gi proteins decreases cAMP
production
• Examples include catecholamine (alpha 2), Ach (M2) etc.
• Receptors linked via G- proteins
• Gq Proteins
• Gq system activates Phospholipase C.
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• Cyclic GMP and Nitric Oxide signaling
• cGMP is a second messenger in vascular smooth muscle that facilitates
dephosphorylation of myosin light chains, preventing their interaction
with actin and thus causing vasodilation.
• NO is synthesized in endothelial cells and diffuses into smooth muscles.
• NO activates guanylyl cyclase, thus increasing cGMP in smooth muscles.
• Receptors that function as transmembrane
enzymes
• Classic example is insulin
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• Receptors for insulin are membrane spanning molecules with recognition
sites for insulin and a cytoplasmic domain that functions as a tyrosine
kinase.
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• Receptors for Cytokines
• These receptors are membrane spanning and on activation can activate a
distinctive set of cytoplasmic tyrosine kinases (janus kinase JAKs)
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• JAKs phosphorylate signal transducers and activators of transcription
(STAT) moecules.
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• Examples include receptors for erythropoietin, somatotropin and
interferons
Signaling Mechanisms & G- Protein coupled
receptors
Signaling Mechanisms
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Binding of an agonist drug to its receptor activates an effector or signaling
mechanism.
Several different types of drug responsive signaling mechanisms are known.
Intracellular receptors
These include receptors for steroids, thyroxine, gonadal steroids and vitamin D.
Binding of drugs or
hormones to such
receptors cause
dimerization of
hormone receptor
complex.
Such complexes translocate to the nucleus, where they interact with response elements
in spacer DNA.
.
This leads to changes in gene expression
Pharmacologic responses elicited via modification of gene expression are slower in
onset but longer in duration.
Membrane receptors directly coupled to ion channels
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Many drugs act by mimicking or antazonizing the actions of endogenous ligands
that regulate flow of ions through excitable membranes via their activation of
receptors that are directly coupled to ion channels
Do not require secondary messengers i.e. directly coupled to ion channels.
Example
Acetylcholine receptors in neuromuscular junction, ANS ganglia and CNS are coupled
to Na ion channels.
Example
GABA receptor in the CNS, which is coupled to a chloride ion channel, can be
modulated by anticonvulsants, benzodiazepines and barbiturates.
Receptors linked via G- proteins
Many receptors are coupled via GTP binding proteins (G-proteins) to adenylyl cyclase,
the enzyme that converts ATP to cAMP, a second messenger that promotes protein
phosphorylation by activating protein kinase A.
These receptors are typically serpentine with 7 transmembrane spanning domains.
Protein kinase A serves to phosphorylate a set of tissue specific substrate enzymes or
transcription factors (CREB), thereby affecting their activity.
Gs Proteins
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Binding of agonists to receptors linked to Gs proteins increases cAMP
production.
Examples include catecholamine (beta receptors), glucagon receptors,
histamine (H2) etc.
Gi Proteins
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Binding of agonists to receptors linked to Gi proteins decreases cAMP
production
Examples include catecholamine (alpha 2), Ach (M2) etc.
Gq Proteins
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Gq system activates Phospholipase C.
Activation of Phospholipase C releases the second messengers inositol
triphosphate (IP3) and diacylglycerol from the membrane phospholipid
phosphatidylinositol biphosphate (PIP2)
The IP3 induces release of Ca+2 from sarcoplasmic reticulum which
together with DAG activates protein kinase C.
Examples: norepinephrine (alpha 1), angiotensin II and several serotonin
subtypes.
Cyclic adenosine monophosphate (cAMP, cyclic AMP
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3'-5'-cyclic adenosine monophosphate) is a second messenger important in
many biological processes.
cAMP is derived from adenosine triphosphate (ATP) and used for intracellular
signal transduction in many different organisms, conveying the cAMP-dependent
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pathway
Cyclic GMP and Nitric Oxide signaling
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cGMP is a second messenger in vascular smooth muscle that facilitates
dephosphorylation of myosin light chains, preventing their interaction with actin
and thus causing vasodilation.
NO is synthesized in endothelial cells and diffuses into smooth muscles.
NO activates guanylyl cyclase, thus increasing cGMP in smooth muscles.
Receptors that function as enzymes or transporters
There are multiple examples of drug action that depend on enzyme inhibition, including
inhibitors of acetylcholinesterase, ACE, carbonic anhydrase etc.
Examples of drug action on transporter systems include inhibitors of reuptake of several
neurotransmitters like dopamine, norepinephrine, GABA etc.
Receptors that function as transmembrane enzymes
Classic example is insulin
Receptors for insulin are membrane spanning molecules with recognition sites for
insulin and a cytoplasmic domain that functions as a tyrosine kinase.
Receptors for Cytokines
These receptors are membrane spanning and on activation can activate a distinctive set
of cytoplasmic tyrosine kinases (janus kinase JAKs)
JAKs phosphorylate signal transducers and activators of transcription (STAT) moecules.
Examples include receptors for erythropoietin, somatotropin and interferons