Pharmacology 3620 Lecture Notes - Lecture 7: Irreversible Antagonist, Intrinsic Activity, Insulin Receptor
1 May 2018
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Lecture 007: Pharmacodynamics II
Objectives
● Describe the 5 major types of antagonists
○ describe the effect that an antagonist has on the dose response curve
● List the four major types of receptors that mediate the effects of drugs
● Describe how ligand gated ion channels mediate drug response
● List the components of GPCRs and the steps in their ligand induced activation
● Define the role of second messengers in GPCR mediated drug action
● Describe the action of enzyme linked receptors (use insulin receptor as example)
● Describe how intracellular receptors mediate drug effects
● List and describe three major pathways in receptor desensitization
● Understand how some drugs mediate their effects without binding to macromolecules
Antagonists
● Blocks the effects of agonists
○ Inhibitors the actions of agonists
● Able to bind to the receptor but don’t activate the receptors when bound
○ Has affinity for the receptor but no intrinsic activity
● Antagonist have no effect in the absence of an agonist
Competitive Antagonist
● Ex. nightlight with no lightbulb
● Binds to the receptor as the agonist but does not
produce an effect in the receptor
○ Has affinity but no intrinsic activity
○ Takes up a receptor from an agonist
● Binding is a reversible process
○ Thus if you increase the concentration of the
agonist you can overcome the effects of a
competitive antagonist
● Presence of a competitive antagonist causes a parallel rightward shift on the dose-
response curve
○ EMAX is the same (maximal efficacy is
UNCHANGED)
○ EC50 is increased
■ Need more of the agonist to produce
the same effect
● Antagonist alone (with no agonist) does not
produce a biological effect
○ Occupies the receptor but does not do anything
● Many drugs acti clinically as competitive antagonist
○ Acetaminophen, statins, beta receptor blockers
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Measuring Competitive Antagonism
● Perform an experiment
● Take a single concentration of the agonist
○ Denote this as 100% effect
● Then vary the concentration of the antagonist
● Plot the % effect of the agonist vs the
concentration of the antagonist
● This determines the IC50
○ Concentration of antagonist required to
produce 50% of inhibition
○ I.e. the functional strength of the
inhibitor
● However, the IC50 be misleading since it
depends on experimental conditions
○ Can use different agonist, concentrations, and substrates working on the same
receptor system
● Thus, the IC50 has to be adjust by the amount of agonist ([S]) used and the affinity of
agonists (Kd) for the receptor
○ Ki is calculated using the Cheng-Prusoff equation
○ Ki represents the binding affinity of the inhibitor
○
Non-Competitive Antagonists
● Occur at either an agonist binding site
(irreversible antagonist) or at an allosteric
site (allosteric antagonism)
● Downward shift of the dose-response curve
○ Decrease the maximal efficacy
○ EC50 remains constant
Irreversible Antagonist
● Bind to the receptor with very high affinity
○ Usually via a covalent bond (can’t be removed)
○ Even at high agonist concentration, they won’t be out-competed
● Irreversibly binds to the receptor
Allosteric Antagonist
● Binds to a site OTHER than the agonist binding site
● Binding either change the conformation of the agonist binding site or prevent the
receptor from being activated even when the agonist is bound
● Can’t increase the agonist concentration to out-compete this kind of binding since it is at
an entirely different binding site
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Non-Receptor Antagonists
● Don’t act on target receptors at all
● Chemical Antagonist
○ Bind and sequester the agonist so that it is unavailable to act on the receptor
● Functional Antagonist
○ Have the other physiological effect to the agonist
○ Still have receptors involved, just not the same target receptors as the agonist
How do Drug-Receptor Complexes Cause a Biological Response?
● Drugs mediate effects by binding to receptors
○ Many effects are mediated by the phosphorylation of a protein (changes its
activity state)
● Have to look at different type of receptors to understand
○ 4 major types of receptor families:
■ Ligand-gated ion channels
■ G-protein coupled receptors
■ Enzyme linked receptors
■ Intracellular receptors
Ligand Gated Ion Channels
● Many cellular process require the passage of ions across the cell
membrane
○ Neurotransmission, cardiac conduction, muscle contraction,
secretion
○ Why this is an important drug target
● Ligand gated ion channels control the flow of ions across the cell membrane
○ Drug/ligand binding opens the ion channel (pores)
○ Some degree in the selectivity of ions that passes through the
pores
● Response to these receptors occurs exceptionally rapid (milliseconds)
Ligand Gated Ion Channels:
1. The Nicotinic Cholinergic Receptor
● 2 molecules of acetylcholine (endogenous agonist) has to bind to the
receptor to open the pore
○ Allows Na+ to rush into the cell
○ Involved in the generation of action potentials and muscle
contractions
● Nicotine is also an agonist (can also bind)
2. The GABAA Receptor
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Document Summary
Describe the 5 major types of antagonists. Describe the effect that an antagonist has on the dose response curve. List the four major types of receptors that mediate the effects of drugs. Describe how ligand gated ion channels mediate drug response. List the components of gpcrs and the steps in their ligand induced activation. Define the role of second messengers in gpcr mediated drug action. Describe the action of enzyme linked receptors (use insulin receptor as example) Describe how intracellular receptors mediate drug effects. List and describe three major pathways in receptor desensitization. Understand how some drugs mediate their effects without binding to macromolecules. Able to bind to the receptor but don"t activate the receptors when bound. Has affinity for the receptor but no intrinsic activity. Antagonist have no effect in the absence of an agonist. Binds to the receptor as the agonist but does not produce an effect in the receptor. Takes up a receptor from an agonist.
