Quiz #2 Material

Question 1

Protein Receptor Signaling Pathways

Answer 1

• Channel-linked receptors
  
  • Milliseconds
  • Nicotinic, Ach receptors
• GPCR
  
  • Seconds
  • Muscarinc, Ach receptors
• Kinase-linked
  
  • Minutes
  • Insulin receptors
• Nuclear receptors
  
  • Hours
  • Estrogen receptor

Question 2

Drugs-Receptor Interactions

Answer 2

• Drug-receptor binding is reversible, bimolecular
  
  • Bimolecular=one drug, one receptor

Question 3

Add drug to a beaker with given concentration of receptors:

Answer 3

• Receptors become saturated at equilibrium
• At equilibrium dissociation and association rates are equal

Question 4

Law of Mass Action

Answer 4

• K1=association rate constant
• K2=dissociation rate constant
• K2/K1=Kd=([D][R])/[DR]
• Kd=equilibrium dissociation constant; a measure of drug’s affinity

Question 5

Fractional Receptor Occupancy

Answer 5

• 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

Question 6

Drug-Binding Curve

Answer 6

• Receptors bounds vs. log scale dose
• Kd=drug concentration to bind 50% of receptors
• Small Kd, greater affinity

Question 7

Drug:Receptor Complex and Drug Effect

Answer 7

• Drug effect is proportional to [Drug:Receptor]
• Max effect when all receptors are bound

Question 8

Efficacy vs. Potency

Answer 8

• 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)

Question 9

Classical Theory of Drug Action: “Occupancy Model”

Answer 9

• [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

Question 10

Affinity vs. Potency

Answer 10

• 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)

Question 11

Types of Agonists:

Answer 11

• 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

Question 12

Drug-Binding curve for partial vs. full agonists:

Answer 12

• Both can still bind 100% of receptors (y-axis)
• Drug with higher affinity will have a lower Kd (curve shifted left)

Question 13

Dose-Response curve for partial vs. full agonists:

Answer 13

• Y-axis is % max response
• Partial agonist will not reach 100% max response
• Drug with higher affinity will be shifted left (lower EC50)

Question 14

Model of Drug-Receptor Action

Answer 14

• 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

Question 15

Drug-Receptor Interactions: Partial, Full and Inverse Agonist

Answer 15

• 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

Question 16

Why is an inverse agonist not called an antagonist?

Answer 16

• Inverse agonist alone is able to produce an effect
• An antagonist exerts an effect only int the presence of an agonist

Question 17

Pharmacodynamics

Answer 17

• Study the action of drugs on the body

Question 18

Competitive Antagonist: Active Site Reversible Binding

Answer 18

• 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

Question 19

Noncompetitive Antagonist: Active Site Irreversible Binding

Answer 19

• 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

Question 20

Varenicline (Chantix) Example:

Answer 20

• 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

Question 21

Noncompetitive Allosteric Antagonist

Answer 21

• 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

Question 22

Summary of Receptor Antagonist Action

Answer 22

• 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

Question 23

Physiological Antagonist

Answer 23

• 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

Question 24

Chemical Antagonist

Answer 24

• Do not interact with a receptor
• Interact directly with the drug/agonist
  
  • 1. Remove the drug from the system
  • 2. 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

Question 25

Therapeutic Considerations:

Answer 25

• 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 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

Question 26

Allosteric Modulators

Answer 26

• Bind to a site on the receptor that is different from the active binding site for the agonist
  
  • 1. Alter the affinity of the agonist for the receptor
  • 2. Alter the level of receptor activation after agonist binding
       * Increase: Positive allosteric modulator
       * Decrease: Negative allosteric modulator

Question 27

Allosteric Modulator Action

Answer 27

• 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

Question 28

Allosteric Modulators of GABA Receptor

Answer 28

• GABA binds; Chloride flows; Inhibits neuronal function
• Midazolam; GABA affinity is higher
  
  • Need less GABA to activate

Question 29

Irreversible Active Site Antagonist

Answer 29

• Decreases max response of agonist
• Looks like potency because of spare receptors

Question 30

Spare Receptors Exist When:

Answer 30

Maximal response to a drug can be achieved when less than all the available receptors are bound by drug

Question 31

Spare receptors lower the agonist concentration required to produce a given response

Answer 31

• To activate two receptors:
  
  • No spare receptors: [Agonist]=Kd
  • With spare receptors: [Agonist] are less than Kd
    *

Question 32

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

Answer 32

• Efficacy: No change
• Potency: Increases
• Affinity: No change

Question 33

Physiological System with Spare Receptors

Answer 33

• 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

Question 34

Why Have Spare Receptors?

Answer 34

• 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
      
      • 1. Spare receptor=sensitivity to low drug concentration
      • 2. 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

Question 35

EC50 and Kd relationship when there are spare receptors

Answer 35

• 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>