Principles of pharmacology - allosteric modulation

Question 1

What are competitive reversible antagonists?

Answer 1

Competes with the agonist for the same binding site, or binds to adjacent site that overlaps.
Antagonist blocks the binding of agonist.
Both bind reversibly.
Binding is mutually exclusive.

Question 2

What does the graph look like when binding is competitive and reversible agonist?

Answer 2

Agonist + agonist requires higher concentration of drug, curve shifts right and parallel, can still produce maximal effect if high enough concentration of agonist.
Agonist + increased [antagonist] = parallel right shift in dose response curve
see graph

Question 3

Is competitive antagonism surmountable?

Answer 3

Competitive antagonism is surmountable because the effects of the antagonist can be overcome by increasing the concentration of the agonist.
Maximal effect is still possible.

Question 4

What are irreversible competitive antagonists?

Answer 4

Compete with agonist for same binding site irreversibly.
Some drugs bind and dissociate so slowly that they produce an irreversible effect.

Question 5

What does the dose response curve look like for irreversible competitive antagonists?

Answer 5

For log dose response graph
Depression in maximal response as concentration of antagonist increases because not enough receptors available.
see graph

Question 6

How is the dose response graph for irreversible competitive antagonists evidence of spare receptors?

Answer 6

The ability to produce maximal response even with antagonist bound is evidence of spare receptors - not all receptors must be bound to produce a maximal response.

Question 7

What are non-competitive antagonists?

Answer 7

Antagonist binds at a different binding site.
Prevents the effect of agonist, without preventing its binding.
Effect is insurmountable, cannot be overcome by increased [agonist].

Question 8

How can partial agonists behave as competitive antagonists?

Answer 8

green is original full agonist
1M partial agonist + full agonist
10M partial agonist + full agonist, full agonist cannot get into the receptor, depression of effect possible.
100M partial agonist + full agonist, full agonist is further depressed as partial agonist is more likely to bind to the receptor.
see graph

Question 9

What is concentration ratio?

Answer 9

The ratio of the concentration of an agonist that produces a specific response (EC50) in the presence of an antagonist, with the agonist concentration that produces the same response in the absence of antagonist.

Question 10

What is the concentration ratio equation?

Answer 10

EC50 agonist in presence of antagonist / EC50 agonist alone.
Can be used to compare effects of antagonists.

Question 11

What are allosteric modulators?

Answer 11

Ligands that bind to a distinct allosteric site on the receptor, different from the agonist binding site.
Ligand binding either increases or decreases the action produced by agonist.

Question 12

How are allosteric modulators better drugs than agonists and antagonists?

Answer 12

Allosteric modulators turn up or down the response, compared to agonists and antagonists which turn things off and on.

Question 13

What does the log dose response graph look like for negative allosteric modulators?

Answer 13

Agonist + NAM = decreased functional response
see graph

Question 14

What does the log dose response graph look like for positive allosteric modulation?

Answer 14

Agonist + PAM = increase in functional response, e.g. by increased agonist binding to receptor
Maximum is always the same

Question 15

What are GABA A receptors?

Answer 15

GABA A receptor is the most common inhibitor in the CNS.
It is a ligand gated ion channel
Causes hyperpolarisation of neurones
Inhibitory effect produced by stimulating GABA A receptors.

Question 16

What is Benzodiazepine receptor?

Answer 16

BZ agonists binding increase the affinity of the GABA site for GABA and therefore increases channel opening.

Question 17

What are Betacarbolines?

Answer 17

Negative allosteric modulator
Bind reversibly at a distinct site from the agonist on the GABA A receptor.
Decreases affinity of agonist binding for agonist.
Reduces likelihood of agonist binding.

Question 18

What are Benzodiazepine receptor ligands?

Answer 18

Agonists - diazepam
Antagonist - flumazenil
Inverse agonist - betacarbolines

Question 19

What are channel blockers?

Answer 19

Bind inside the channel and prevent the passage of ions.
Binding of channel blockers tends to be enhanced by receptor activation.
Use dependent block - channel must be open for PCP to enter and bind.
e.g. phencyclidine (PCP) at the NMDA receptor.

Question 20

What are physiological antagonists?

Answer 20

Produce opposite effects on a tissue.
Produce a non-selective suppression of the response.
e.g. acetylcholine and adrenaline

Question 21

What is desensitisation?

Answer 21

Prolonged or repeated exposure to an agonist reduces the response to that drug.
e.g. opiate drugs of abuse, like heroin
e.g. inactivation of nicotinic receptor - the receptor is driven into an inactivated state.

Question 22

How does desensitisation occur?

Answer 22

Effects through inhibition of 2nd messenger
Prolonged agonist exposure -> upregulation of 2nd messenger
Increased [agonist] required to produce same level of inhibition