Quiz #2 Material Flashcards
Protein Receptor Signaling Pathways
- Channel-linked receptors
- Milliseconds
- Nicotinic, Ach receptors
- GPCR
- Seconds
- Muscarinc, Ach receptors
- Kinase-linked
- Minutes
- Insulin receptors
- Nuclear receptors
- Hours
- Estrogen receptor
Drugs-Receptor Interactions
- Drug-receptor binding is reversible, bimolecular
- Bimolecular=one drug, one receptor
Add drug to a beaker with given concentration of receptors:
- Receptors become saturated at equilibrium
- At equilibrium dissociation and association rates are equal
Law of Mass Action
- K1=association rate constant
- K2=dissociation rate constant
- K2/K1=Kd=([D][R])/[DR]
- Kd=equilibrium dissociation constant; a measure of drug’s affinity
Fractional Receptor Occupancy
- Rearrange Law of Mass Action
- [DR]/[Rt]=[D]/(Kd+[D])
- Fraction of the receptors bound by drugs depends only on [D] and Kd
- When the concentration of the drug equals Kd, 50% of receptors will be bound by drug
- Drug is always in excess so that you’ll always get the same FRACTION that binds
- Doesn’t matter how many receptors are in the system
Drug-Binding Curve
- Receptors bounds vs. log scale dose
- Kd=drug concentration to bind 50% of receptors
- Small Kd, greater affinity

Drug:Receptor Complex and Drug Effect
- Drug effect is proportional to [Drug:Receptor]
- Max effect when all receptors are bound
Efficacy vs. Potency
- Emax=max effect of drug=efficacy
-
Potency=EC50=drug that produce 50% of effect
- Smaller EC50 means a more potent drug
- Do you prescribe a more potent drug or a more efficacious drug?
- Depends on magnitude of change that you want (disregarding toxicities)

Classical Theory of Drug Action: “Occupancy Model”
- [D]+[R]→Kd→[DR]—–→Response
- Assumptions
- Simple, bimolecular reaction that is reversible
- Magnitude of response proportional to [drug:receptor]
- effect=[RD]
- Max response when all receptor occupied
- Emax=100% occupancy
Affinity vs. Potency
- Affinity
- Drugs ability to bind receptor
- Defined by Kd
- Potency
- Amount of drug to produce effect
- Defined by EC50
- Can conclude that Kd=EC50
- Drugs with higher affinity are more potent
- (True in most cases, but sometimes it doesn’t signal)
- Drugs with higher affinity are more potent
Types of Agonists:
-
Full agonist:
- Produce maximal effect
- Will always have a higher efficacy than a partial agonist, however WILL NOT always be more potent than a partial agonist
-
Partial agonists
- Lower efficacy than full agonist
- Cannot produce max effect even when all receptors are bound
-
Inverse agonists
- Reduce the low level of constitutive/basal activity observed in the absence of any agonist
Drug-Binding curve for partial vs. full agonists:
- Both can still bind 100% of receptors (y-axis)
- Drug with higher affinity will have a lower Kd (curve shifted left)

Dose-Response curve for partial vs. full agonists:
- Y-axis is % max response
- Partial agonist will not reach 100% max response
- Drug with higher affinity will be shifted left (lower EC50)

Model of Drug-Receptor Action
- Two Receptor Conformations
- Ri = inactive form that produces no effect when bound by agonist
- Ra = active form that produces a small effect in absence of bound agonist
Drug-Receptor Interactions: Partial, Full and Inverse Agonist
- Full agonist
- much higher affinity for Ra than for Ri
- Partial agonist
- somewhat higher affinity for Ra than for Ri
- Inverse agonist
- much higher affinity for Ri than for Ra

Why is an inverse agonist not called an antagonist?
- Inverse agonist alone is able to produce an effect
- An antagonist exerts an effect only int the presence of an agonist
Pharmacodynamics
- Study the action of drugs on the body
Competitive Antagonist: Active Site Reversible Binding
- Antagonist binding does not activate the receptor
- Shifts dose-response curve to the right
- Decreases potency of agonist (Increase EC50)
- No change in efficacy (Emax)
- Surmountable: Effects of competitive antagonist can be overcome by increasing agonist concentration

Noncompetitive Antagonist: Active Site Irreversible Binding
- Covalent bond
- Reduces total number of receptors available for agonist binding
- Shifts the dose-response curve downward
- Reduces efficacy of agonist
- No change in potency
-
Insurmountable: Effects of irreversible antagonist cannot be overcome by increasing concentration of agonist
- # of receptors decreases→have to make more

Varenicline (Chantix) Example:
- Partial agonist at nicotinic receptors in the brain
- Binds to nicotine receptors
- Effect in brain is less than nicotine because it is a partial agonist
- Acts like a competitive antagonist against nicotine to outcompete nicotine at the receptor
- Reduces the max effect of A
- B is a competitve antagonist agains tthe copetitve antagonist of A. B alone=partial agonist

Noncompetitive Allosteric Antagonist
- Binds to receptor at site different from agonist
- Does not bind to the active site
- Blocks the responsiveness of the receptor to agonist
- Prevents binding of agonist to active site of receptor
- Abolishes activation of the receptor after agonist binds
- See a decrease in the max response
- It is A+D in figure below

Summary of Receptor Antagonist Action
- Competitive antagonist
- Decreases potency
- Binds reversibly to active site of receptor
- Noncompetitive active site antagonist
- Decreases efficacy
- No effect on potency because the affinity for the receptor is the same. 50% of the lower efficacy is the same as 50% of the higher efficacy
- Binds irreversible to active site of receptor
- Noncompetitive allosteric antagonist
- Decreases efficacy
- Binds reversibly or irreversibly to site other than active site of receptor
Physiological Antagonist
- Agonist and antagonist bind two different receptors
- Activation of the two receptors produces opposing physiological effects
- Effects that cancel each other out
- I.e. Elevated glucocorticoid levels can lead to hyperglycemia. Administer insulin as physiological antagonist to reduce blood sugar levels
- Physiological antagonists bind to a receptor and produce an effect
- Differ from all other antagonists
Chemical Antagonist
- Do not interact with a receptor
- Interact directly with the drug/agonist
- Remove the drug from the system
- Prevent the drug from binding to its receptor
- Gets eliminated or secreted from the body
- Decreases drug concentration in the body
- Examples:
- Protamine sulfate: stably bind to heparin and reverses anti-coagulant effects
- Dimercaprol: binds to toxic metals which are then excreted in the urine
Therapeutic Considerations:
- Patient with bradycardia caused by increased release of acetylcholine from vagus nerve endings
- Administer isoproterenol, agonist for beta-adrenergic receptor that increases heart rate (different receptor)
- Physiological antagonist
- Administer isoproterenol, agonist for beta-adrenergic receptor that increases heart rate (different receptor)
- Administer atropine, which binds the active site and block the receptors at which acetylcholine acts to slow heart rate
- Competitive antagonist
- Could also be irreversible active site antagonist (Noncompetitive antagonist)
- Need more information to determine
Allosteric Modulators
- Bind to a site on the receptor that is different from the active binding site for the agonist
- Alter the affinity of the agonist for the receptor
- Alter the level of receptor activation after agonist binding
* Increase: Positive allosteric modulator
* Decrease: Negative allosteric modulator
- Alter the level of receptor activation after agonist binding
Allosteric Modulator Action
- Positive Modulator: Affinity
- Increases affinity of agonist for receptor
- Increases potency
- Positive Modulator: Action
- Increases level of receptor activation by agonist
- Increases efficacy
- Negative Modulator: Affinity
- Decreases affinity of agonist for receptor
- Decreases potency
- Negative Modulator: Activation
- Decreases level of receptor activation by agonist
- Decreases efficacy
Allosteric Modulators of GABA Receptor
- GABA binds; Chloride flows; Inhibits neuronal function
- Midazolam; GABA affinity is higher
- Need less GABA to activate
Irreversible Active Site Antagonist
- Decreases max response of agonist
- Looks like potency because of spare receptors

Spare Receptors Exist When:
Maximal response to a drug can be achieved when less than all the available receptors are bound by drug
Spare receptors lower the agonist concentration required to produce a given response
- To activate two receptors:
- No spare receptors: [Agonist]=Kd
- With spare receptors: [Agonist] are less than Kd
*

Total receptor concentration for morphine is X and the max response requires X receptors to be bound. Treatment with naltrexone, a morphine receptor antagonist, leads to a 50% increase in total number of receptors.
What effects does the increase in receptor concentration have on morphine’s:
- Efficacy
- Potency
- Affinity
- Efficacy: No change
- Potency: Increases
- Affinity: No change
Physiological System with Spare Receptors
- Leydig cells
- Adjacent to seminiferous tubules in the testicle
- Express receptors for LH
- Produce testosterone and other steroid hormones in response to LH
- Max hormone production observed with 1% of LHR bound by agonist
- LHR is a GPCR that activates AC
- Reach amount of cAMP needed for hormone response with only 1% LHR activated
- When the number of receptors exceeds the number of effector molecules
- 40 GPCR but only 4 G-proteins
- Max response needs all 4 G-proteins activation
- Only 10% receptor occupancy necessary to produce the max response
Why Have Spare Receptors?
- Potential protective effect
- Spare receptors bind up extra agonist without producing any additional response
- (1) Increase the sensitivity of the system for agonist
- (2) Protective effect
- (3) Allows for rapid onset and termination of a desired response (such as in neurotransmission)
- Obtain desired response at very low concentrations of an agonist that has a relatively low affinity
- Spare receptor=sensitivity to low drug concentration
- Low affinity=more rapid dissociation and termination of the response
- Drug is floating on and off; get a signal turned on at low concentration but then turned off quickly
- Obtain desired response at very low concentrations of an agonist that has a relatively low affinity
EC50 and Kd relationship when there are spare receptors
- EC50<kd>
</kd><li>Increases drug potency</li><li>Spare receptors are present when maximal drug response can be achieved with less than 100% of the receptors bound by drug </li>
</kd>