PHSC1613 Pharmacology - Lecture 3 Ligand-Receptor Theory: Antagonists

Antagonist won't produce effect

Why could the ligand on an effect curve only be an agonist?

Antagonists

bind to receptors but do not activate them; primary action is to reduce the effects of agonists or some can reduce basal activity

Reduce effects of agonists

primary action of antagonists

Inverse agonists

"antagonists" that also reduce basal (constitutive) activity

Competitive and Noncompetitive

two modes of action of antagonists

Competitive antagonism

occurs when the agonist and antagonist compete for the same binding site on the receptor

Agonist and antagonist compete for the same binding site

What happens in competitive antagonism?

Orthosteric

site that the competitive antagonist binds at

Reversible

Is binding in competitive antagonism reversible or irreversible?

EC50 or Kd

increases for the agonist in the presence of a competitive antagonist

Emax or Bmax

remains unchanged in the presence of a competitive antagonist

Requires more concentration but can reach same effect or binding

Why does EC50 or Kd increase while Emax and Bmax remain unchanged for an agonist in the presence of a competitive antagonist?

Compete the antagonist off the receptor

What can a high enough concentration of agonist do if there is a competitive antagonist?

Shifted to the right

What happens to response or binding curves for an agonist with increasing concentrations of the antagonist?

Binding curve

What type of curve would look at percent occupancy?

Concentrations of antagonist and agonist

What does the degree of inhibition produced by a competitive antagonist depend on?

Reduce agonist effect to zero

In competitive antagonism, a high enough concentration of antagonist with a given concentration of agonist can do what?

IC50

antagonist concentration corresponding to 50% inhibition of agonist

No, they can vary between and within individual patients

Are endogenous agonist levels the same for everyone?

Partial agonist

a type of agonist that can also compete with a full agonist for binding to the receptor and in this case, it would behave as a competitive antagonist

Competitive antagonist

A partial agonist competing with a full agonist for receptor binding is behaving as a what?

Reduce effect to zero

While a partial agonist can compete with a full agonist behaving similarly to a competitive antagonist, what can the partial agonist not do?

It has its own efficacy

Why can't a partial agonist reduce the effect to zero?

Irreversible and allosteric

two types of noncompetitive antagonists

Irreversible

antagonist that covalently binds to the same site as the agonist

Covalently at the same site as the agonist

How does an irreversible noncompetitive antagonist bind?

It binds permanently/covalently

Why can't an irreversible noncompetitive antagonist be overcome by increasing agonist concentration?

New receptor production

How can receptor activity be restored after a noncompetitive antagonist binds?

Allosteric

antagonist that reversibly binds to a different site on the receptor

Reversibly at a different site from the agonist

How does an allosteric noncompetitive antagonist bind?

Decreases agonist efficacy, may influence agonist affinity

functions of an allosteric antagonist

Reduces its ability to shift receptors into active conformation or ability to activate effector

How does an allosteric antagonist decrease the efficacy of the agonist?

Cannot be competed off the receptor by agonist

Why is the overall effect of an allosteric antagonist similar to an irreversible antagonist?

Until drug receptor complex is destroyed and new receptors or enzymes are synthesized

How long does the effect of an irreversible antagonist persist?

Emax or Bmax

progressively decrease with increasing concentrations of noncompetitive irreversible antagonist

EC50, not Kd, will shift to the right before Emax begins to decrease

What happens to EC50 if there are spare receptors and increasing concentrations of a noncompetitive irreversible antagonist?

Response or occupancy curves for agonist

shifted downward with increasing concentrations of noncompetitive irreversible antagonist

Response, not occupancy, curve initially shifts right and then downward

What happens to response and occupancy curves if there are spare receptors and increasing concentrations of a noncompetitive irreversible antagonist?

By reducing efficacy or affinity

How can negative allosteric modulators (noncompetitive allosteric antagonists act?

EC50 stays the same while Emax decreases

If the noncompetitive allosteric antagonist doesn't reduce affinity of the agonist for receptor, what happens to the EC50 and Emax as antagonist concentrations increase?

EC50 increases while Emax decreases

If the noncompetitive allosteric antagonist also reduces affinity of the agonist for receptor, what happens to the EC50 and Emax as antagonist concentrations increase?

Shifted downward

If the noncompetitive allosteric antagonist doesn't reduce affinity of the agonist for receptor, what happens to the response curve as antagonist concentrations increase?

Shifted right and downward

If the noncompetitive allosteric antagonist also reduces affinity of the agonist for receptor, what happens to the response curve as antagonist concentrations increase?

Indirect agonism

when some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist

Some drugs have agonist response by inhibiting termination of endogenous agonist

How does indirect agonism work?

Blocking its metabolism or transport

How might a drug prevent removal of an endogenous agonist in indirect agonism?

Cholinesterase and Serotonin transporter inhibitors

examples of types of drugs that exhibit indirect agonism

Cholinesterase inhibitors

prevent breakdown of acetylcholine (ex. donepezil)

Donepezil

cholinesterase inhibitor drug example

Serotonin transporter inhibitors

inhibit neuronal reuptake of serotonin (ex. sertraline)

Sertraline

serotonin transporter inhibitor drug example

Antagonists, agonist, endogenous agonist

Drugs that display indirect agonism act as _________ of their target proteins but ultimately have ________ effects on a receptor by increasing concentrations of ___________________