2. Receptors Ii

Front 1

What is the general definition of an Antagonist?

Back 1

A molecule that inhibits or blocks the effects of an agonist.

Front 2

3 general types of antagonists:

Back 2

-Chemical
-Physiological
-Pharmacological

Front 3

What is a chemical antagonist?

Back 3

One that actually combines with an agonist, preventing it from interacting with its target site of action.

Front 4

What is an example of a chemical antagonist?

Back 4

Protamine - binds/inactivates heparin.

Front 5

How do Physiological Antagonists work?

Back 5

By activating opposing physiological inputs

Front 6

What is an example of a physiological antagonist/agonist pair?

Back 6

Sympathetic NE and Parasympathetic ACh regulation of heartrate

Front 7

Is NE a pharmacological antagonist?

Back 7

No; it's actually an agonist of the adrenergic receptor.

Front 8

What is a Pharmacological antagonist?

Back 8

One that blocks the effects of an agonist at its site of action

Front 9

What makes Antagonists different from agonists?

Back 9

Antagonists have no intrinsic activity at all; binding to the receptor has no effect other than to prevent an agonist from binding.

Front 10

2 What 2 things is a response to a compound binding its receptor proportional?

Back 10

1. Fraction of occupied receptors
2. Intrinsic activity

Front 11

What is Intrinsic activity?

Back 11

Emax of compound of interest
----------------------------
maximum Emax

Front 12

2 General categories of Antagonists:

Back 12

-Competitive
-Noncompetitive

Front 13

What is the difference between competitive and noncompetitive antagonists?

Back 13

-Competitive bind to the exactly same site on the receptor as the agonist
-Noncompetitive bind to a different site than the agonist

Front 14

What are 2 types of Competitive antagonists?

Back 14

-Competitive Equilibrium antagonists
-Competitive Nonequilibrium antagonists

Front 15

What makes Competitive equilibrium antagonists unique?

Back 15

They are reversible and can be surmounted by increasing the agonist concentration

Front 16

What makes Competitive nonequilibrium antagonists unique?

Back 16

They are nonreversible and cannot be surmounted by increasing the agonist.

Front 17

What is EC50?

Back 17

The concentration of a drug that produces 50% of max effect.

Front 18

How does a competitive equilibrium antagonist alter the concentration/effect curve?

Back 18

It increases the EC50 and shifts the curve to the right.

Front 19

What do we call an EC50 after it has been increased by a competitive equilibrium antagonist?

Back 19

EC50'

Front 20

What is the Kd of an antagonist called?

Back 20

Ki

Front 21

What is Ki?

Back 21

The dissociation constant of an antagonist.

Front 22

What is the equation for calculating the new EC50' after adding a competitive equilibrium antagonist?

Back 22

[Antagonist]
EC50' = EC50 (1 + (------------)
Ki

Front 23

What happens to the change in EC50 of an agonist as the Ki of the antagonist increases?

Back 23

The EC50 changes less, because the antagonist has a tendency to dissociate and is hence weak.

Front 24

What happens to the change in EC50 of an agonist as the concentration of antagonist increases?

Back 24

The EC50 increases more

Front 25

So the ability of an agonist to produce a response in the presence of a competitive equilibrium antagonist is dependent upon what 2 things?

Back 25

-Concentration of antagonist
-Affinity of the antagonist for the receptor (1/Ki)

Front 26

What is the amount of inhibition caused by a competitive equilibrium antagonist dependent upon?

Back 26

-Concentration of agonist
-Concentration of antagonist

Front 27

When comparing two competitive equilibrium antagonists, what will make one able to produce greater inhibition, all else being equal?

Back 27

Lower Ki (higher affinity)

Front 28

What is the 2nd type of competitive antagonist?

Back 28

Nonequilibrium, nonsurmountable, irreversible.

Front 29

What makes a nonequilibrium competitive antagonist irreversible?

Back 29

It binds the receptor covalently

Front 30

What effect do nonreversible competitive antagonists have on the system?

Back 30

They reduce the receptor pool

Front 31

How does a nonreversible competitive antagonist alter the effect vs: concentration curve when spare receptors are present?

Back 31

It increases the EC50 and shifts the curve to the right, just the same as for an equilibrium reversible antagonist.

Front 32

How does a nonreversible competitive antagonist alter the effect vs: concentration curve when spare receptors are NOT present?

Back 32

It does not shift the curve to the right, but simply decreases the Emax that can be produced by the agonist.

Front 33

How does a nonreversible competitive antagonist alter the EC50 when spare receptors are not present?

Back 33

It does not alter the EC50

Front 34

What is the only way to overcome the effects of a nonreversible competitive antagonist?

Back 34

Synthesize new receptors

Front 35

If you were to compare Conc vs Effect curves for a competitive reversible and irreversible antagonist in the presence of spare receptors, how could you tell them apart?

Back 35

By adding the antagonist, washing it off, and then re-analyzing the curve.

Front 36

What happens to each type of competitive antagonist when you wash the system?

Back 36

-Reversible gets washed off so you don't see any antagonism
-Irreversible won't wash off, so you continue to see the antagonistic effect

Front 37

What is a clinical condition in which an irreversible antagonist is a good drug?

Back 37

Pheochromocytoma - by irreversibly inhibiting the alpha-adrenergic receptor with Phenoxybenzamine

Front 38

Why is the irreversible inhibition of alpha-adrenergic receptors with Phenoxybenzamine a good way to treat Pheochromocytoma?

Back 38

Because even if you get sudden spikes in the agonists NE/Epi, you won't see sudden spikes in blood pressure.

Front 39

What is the predominant difference in a noncompetitive antagonist compared to competitive?

Back 39

It blocks the effects of agonist activation of a receptor at a site OTHER than the binding site.

Front 40

If a noncompetitive antagonist does not prevent L+R from forming LR complexes, how does it act as an antagonist?

Back 40

It prevents transduction of the LR complex into an effect.

Front 41

What does the agonist concentration curve for a noncompetitive antagonist look like?

Back 41

Same as for an irreversible competitive antagonist
-No change in EC50
-Decreased Emax

Front 42

What are the 2 main therapeutic implications of noncompetitive antagonists?

Back 42

1. Antagonist effect is essently independent of the [agonist]
2. Can use it to inhibit multiple agonists that use the same signal transduction cascade

Front 43

Does the presence of spare receptors change how a noncompetitive antagonist will alter the agonist concentration curve?

Back 43

No; it will always just lower the Emax and leave the EC50 unchanged.

Front 44

What are 2 ways that you could differentiate a noncompetitive antagonist from an equilibrium reversible antagonist?

Back 44

1. Noncompetitive has NO Ki
2. Wash experiment - both would wash off

Front 45

What is a partial agonist?

Back 45

A ligand with affinity for a receptor, and intrinsic activity between 0 and 1

Front 46

What effect is seen when a partial agonist is present alone?

Back 46

Agonist-like

Front 47

What effect is seen when a partial agonist is present with a full agonist?

Back 47

An antagonist effect

Front 48

What are receptors like normally?

Back 48

Tonically, constitutively active

Front 49

What is the theory for how agonists actually work?

Back 49

Bind the active form of a receptor and stabilize it

Front 50

What is a molecule that binds the inactive form of a receptor and stabilizes it?

Back 50

An inverse agonist

Front 51

What is the difference between an inverse agonist and an antagonist?

Back 51

Inverse agonists cause a change in the receptor - stabilizing it in the inactive form; Antagonists cause NO change in the receptor at all.