BPS2012 Pharmacology II: Drug Action HD 85 notes
Agonists
- Receptor occupation / Drug-receptor complex formation
- Note: Ligand = agonist or antagonist
- If the ligand is an agonist, the formation of a ligand-receptor complex
initiates a receptor-mediated pharmacological activity
- Law of mass action
- Assumptions:
- Receptors are free or bound
- Ligands can freely access receptors
- Binding is reversible
- Ligand-receptor complex formation does not change either the
receptor or liinverse gand (agonist - receptor binding doesn't change
either the receptor or agonist)
-
- Forward reaction
- k1 = association rate constant
-
- Backward reaction
- k2 = dissociation rate constant
-
- Equilibrium
-
- Dissociation constant
- Concentration of agonist required to produce 50% of the
maximal response receptor sites at equilibrium (EC50) =
represents affinity of a receptor for an agonist
- Hill-Langmuir equation
, BPS2012 Pharmacology II: Drug Action HD 85 notes
-
- Ka = EC50 = concentration of drug required to occupy 50% of
the receptor sites at equilibrium (equilibrium constant)
- Refers to the effect of an agonist on receptor sites
- IC50 = concentration of a drug needed to inhibit a response by
50% (half-maximal inhibitory concentration)
- Refers to potencies of antagonist on receptor sites
- Pa = proportion of receptor occupied / response
-
- pD2 = EC50
- Reasons for a maximal response (maximum response = 1)
- All receptors are occupied = receptor saturation
- Internal cellular machinery could be fully responding
(contraction mechanism saturated) = saturation
- Definitions
- Affinity → extent to which a ligand binds to a receptor and forms a complex at
a given concentration: the strength of binding
- Potency → proportional to affinity, thus stronger a drug or ligand binds, the
less concentration is needed to produce a response
- Efficacy → ability of the agonist-receptor complex to elicit a response from
the cell or tissue. Note: also intrinsic efficacy or activity
, BPS2012 Pharmacology II: Drug Action HD 85 notes
Partial agonists
-Both full and partial agonists bind with equal strength to the receptor
-Full and partial agonists elicit different responses
-Partial agonists are weaker activators of signaling, thus regardless of
the concentration, they will never produce a maximal response
- 1956, Stephenson suggested a measure of agonist activity = efficacy
- Efficacy = capacity to initiate a response once it occupies a receptor
- Assumptions to elicit an effect, an agonist must:
- Bind to a receptor = affinity
- Activate the receptor = efficacy
- Two-state model
-
- Includes both affinity (occupation) and efficacy (activation)
- Assumes the tendency for the agonist-receptor complex to convert to the
agonist-receptor complex's active state depends on the beta-alpha reaction's
equilibrium constant.
- Agonists with high efficacy with have a high beta-alpha, whereas partial
agonist that cannot elicit a maximal response has lower efficacy and thus low
beta alpha
- Inverse agonist binds to active complex and actively shifts complex to
inactive complex
- Efficacy = ratio of a partial agonist maximum response / full agonist
maximum response
- Response
-
- To compare different response curves use this equation
- * = properties of tissues
- ** = properties of agonist-receptor interaction
- Agonist and Inverse Agonist + Constitutive activity
, BPS2012 Pharmacology II: Drug Action HD 85 notes
- An inverse agonist is a ligand that binds to the same receptor-binding site as
an agonist and not only antagonizes the effects of an agonist but, moreover,
exerts the opposite effect by suppressing spontaneous receptor signaling
-
- Constitutive activity = Receptors can be active without an agonist
- Sometimes “agonists” might switch receptors off
- Antagonists blocking binding site for agonists and inverse agonists to
use
-
- Inverse agonist binds preferentially to R and will actively shift
receptors from R* to R (active to resting state)
- Agonist binds preferentially to R (given higher affinity for R) and
actively shift receptors from R to R* (resting to active state)
- The pure antagonist has no preference for (active or resting state) R
or R*. When it binds there is no change in the receptor activity
- Ternary complex model
Agonists
- Receptor occupation / Drug-receptor complex formation
- Note: Ligand = agonist or antagonist
- If the ligand is an agonist, the formation of a ligand-receptor complex
initiates a receptor-mediated pharmacological activity
- Law of mass action
- Assumptions:
- Receptors are free or bound
- Ligands can freely access receptors
- Binding is reversible
- Ligand-receptor complex formation does not change either the
receptor or liinverse gand (agonist - receptor binding doesn't change
either the receptor or agonist)
-
- Forward reaction
- k1 = association rate constant
-
- Backward reaction
- k2 = dissociation rate constant
-
- Equilibrium
-
- Dissociation constant
- Concentration of agonist required to produce 50% of the
maximal response receptor sites at equilibrium (EC50) =
represents affinity of a receptor for an agonist
- Hill-Langmuir equation
, BPS2012 Pharmacology II: Drug Action HD 85 notes
-
- Ka = EC50 = concentration of drug required to occupy 50% of
the receptor sites at equilibrium (equilibrium constant)
- Refers to the effect of an agonist on receptor sites
- IC50 = concentration of a drug needed to inhibit a response by
50% (half-maximal inhibitory concentration)
- Refers to potencies of antagonist on receptor sites
- Pa = proportion of receptor occupied / response
-
- pD2 = EC50
- Reasons for a maximal response (maximum response = 1)
- All receptors are occupied = receptor saturation
- Internal cellular machinery could be fully responding
(contraction mechanism saturated) = saturation
- Definitions
- Affinity → extent to which a ligand binds to a receptor and forms a complex at
a given concentration: the strength of binding
- Potency → proportional to affinity, thus stronger a drug or ligand binds, the
less concentration is needed to produce a response
- Efficacy → ability of the agonist-receptor complex to elicit a response from
the cell or tissue. Note: also intrinsic efficacy or activity
, BPS2012 Pharmacology II: Drug Action HD 85 notes
Partial agonists
-Both full and partial agonists bind with equal strength to the receptor
-Full and partial agonists elicit different responses
-Partial agonists are weaker activators of signaling, thus regardless of
the concentration, they will never produce a maximal response
- 1956, Stephenson suggested a measure of agonist activity = efficacy
- Efficacy = capacity to initiate a response once it occupies a receptor
- Assumptions to elicit an effect, an agonist must:
- Bind to a receptor = affinity
- Activate the receptor = efficacy
- Two-state model
-
- Includes both affinity (occupation) and efficacy (activation)
- Assumes the tendency for the agonist-receptor complex to convert to the
agonist-receptor complex's active state depends on the beta-alpha reaction's
equilibrium constant.
- Agonists with high efficacy with have a high beta-alpha, whereas partial
agonist that cannot elicit a maximal response has lower efficacy and thus low
beta alpha
- Inverse agonist binds to active complex and actively shifts complex to
inactive complex
- Efficacy = ratio of a partial agonist maximum response / full agonist
maximum response
- Response
-
- To compare different response curves use this equation
- * = properties of tissues
- ** = properties of agonist-receptor interaction
- Agonist and Inverse Agonist + Constitutive activity
, BPS2012 Pharmacology II: Drug Action HD 85 notes
- An inverse agonist is a ligand that binds to the same receptor-binding site as
an agonist and not only antagonizes the effects of an agonist but, moreover,
exerts the opposite effect by suppressing spontaneous receptor signaling
-
- Constitutive activity = Receptors can be active without an agonist
- Sometimes “agonists” might switch receptors off
- Antagonists blocking binding site for agonists and inverse agonists to
use
-
- Inverse agonist binds preferentially to R and will actively shift
receptors from R* to R (active to resting state)
- Agonist binds preferentially to R (given higher affinity for R) and
actively shift receptors from R to R* (resting to active state)
- The pure antagonist has no preference for (active or resting state) R
or R*. When it binds there is no change in the receptor activity
- Ternary complex model
