Download Receptor Antagonists Competitive Antagonist • drug acts at the

Receptor Antagonists
Competitive Antagonist
• drug acts at the same receptor and competes with the agonist
for the active site (or orthosteric binding site)
Non-Competitive Antagonist
• binding at an allosteric binding site
o may impact the affinity or efficacy of agonist binding
Competitive
Antagonist
Ø binds to the orthosteric site
Ø copetitive antagonist occupes site but does not generate a
stimulus
o No stimulus à no ion flux à no response
Reversible
• Only one drug can be at a receptor at any one time.
• At any given concentration of antagonist, there will be fewer
receptors available for binding of the agonist ∴ fewer
agonist-receptor complexes ∴ reduced response
• If we increase [agonist], they can out-compete the antagonist
o Antagonist effect is reversible (or summountable) by ↑ [agonist]
• In realtiy, while some antagonists are reversible, they can take some time to be reversed
o ∴ effects of an antagonist usually lasts longer than the effects of an agonist
Irreversible
• Antagonist has a stronger bond (covalent) to the receptor compared to the agonist
• Fewer receptors available to bind to and ↑ [agonist] does not allow agonist to bind thus does
not increase response (insummountale or irreversible)
Antagonists alter the action of an agonist actng t the same receptor
à alter the position or shape of the log CR curve
Learning Objectives
describe how Occupation Theory-based receptor models have evolved and shaped our understanding of agonist actions
explain the concepts of efficacy, partial agonists, spare receptors and inverse agonists
explain the effects of competitive receptor antagonists on agonist CR curves
Efficacy
Clinical efficacy: “the power to produce an effect”
• e.g. does it alter blood pressure, etc.
cf: clinical efficacy
Ability of a drug, once bound, to activate the receptor to cause a response
Receptor occupancy vs Response
Occupation Theory
Models
Clark’s Model
• response determined by the proportion of receptors occupied by the drug
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o i.e response =
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• maximal response occurs when all receptors are occupied
o i.e. Emax ∝ [R]total à response depends on number of receptors in the tissue
o relationship between occupancy & response is direct and linear
Implies:
• maximum response is a property of the tissue
• all agonists will have the same maximum response
BUT:
The NeuroMuscular Junction (NMJ) has ~ 30,000,000 AcetyCholine (Ach) receptors
- activation of only 40,000 required for Action Potential (twitch of muscle fibre)
o some receptors are inactivated at times. If we only had exactly how much we need, as
soon as the inactivation process begins, we will have some drastic conseuqences in the
tissue
- receptor reserve in tissues (approx. 100-1000X what is required)
Spare Receptors
..in excess of those needed to produce a maximum response
• If a full agonist requires occupation of only 5% of the available receptors in order to produce a
maximal response, then 95% of receptors are spare receptors for that agonist.
⇒ there is a receptor reserve of 95% for that agonist.
Drugs acting on the same receptor but producing different maximum responses.
à not all drugs are equal
Modification to
Clark’s Model
Ariens (1954) and Stephenson (1956):
Response: [DR] / [R]total
‘intrinsic efficacy’
Full Agonist
Partial Agonist
• some agonists can produce a maximal response when occupying fewer than 100% of receptors
à “full” agonist
• some agonists need to occupy all (or a greater proportion of) receptors in order to produce a
maximal response à “partial” agonist
Further
Modifications
RF Furchgott:
• “Efficacy” is determined by both the intrinsic efficacy of the drug (ε) and the receptor density
(total amount of receptors [R]total)
T Kenakin:
• Mathematical modelling....
Current Thinking
maximum response of a tissue to a drug is determined by:
[R]total & coupling between receptor & response à(tissue characteristics)
AND
Efficacy à(drug characteristic)
• in a tissue with a lot of spare receptors, a partial agonist may appear as a full-agonist
Studying Agonists
ConcentrationResponse Curves
We can plot data as:
• absolute response (tension) in grams
• response as a % of maximum
Partial Agonists
Partial Agonists:
ü have affinity
ü have efficacy, but LOWER than that of a full agonist
o unable to activate the receptor to the full extent
Efficacy
≠
Occupancy
Efficacy
≠
Potency
Efficacy refers to the ability of the drug, once bound, to activate the
receptor whereas potency refers to how much of the drug is required to
produce a particular effect.
Efficacy is measured by Emax
Potency is measure by EC50
Efficacy: L=N > M
Potency: L>M>N
What determines
efficacy?
different conformational states of R* (activated receptor)
ü determined by ligand
ü can influence signalling (e.g. GPCRs)
Spare Receptors
and
Partial Agonists
In a tissue, where there is no spare receptors, a partial agonist cannot cause a maximal response even if it
is bound to all receptors.
If an agonist is a partial agonist, but the tissue has lots of reserve (spare) receptors, a partial agonist may
appear to be a full agonist because it can cause a maximal response
Selectivity
• most drugs can interact with
>1 receptor to produce
multiple effects
• effects determined by affinity
and efficacy at each receptor
if we show that different
concentrations cause different
responses, we can show some
selectivity for the drug…at low
concentrations, we can have one effect
but not another…as concentration
increases, we get more responses
Studying Antagonists
Start of with a known agonist.
When we add antagonist, the curve should shift to the right.
Competitive
Reversible
Antagonists
• competes with agonist for SAME site on receptor
o the one that gets to the receptor most is the one that has the highest concentration
• surmountable – ie ↑ [agonist] can ‘overcome’
• reversible on washing
Effect on agonist CR curve?
ü ü ü ü Competitive
Irreversible
Antagonists
Parallel shift to the right
Same Emax
Same efficacy
↑ EC50 (reduced potency) ∴ ↓pEC50
• dissociates slowly from the binding site
• essentially insurmountable
• essentially irreversible
o reducing number of receptors (inactiviating them so they are not available to the agonist).
o if we have enough antagonist, we will get no response.
Effect on agonist CR curve?
ü ↓ Emax with increasing [antagonist]
e.g. PBZ (phenoxybenzamine)
• interacts with a range of receptors
o ACh receptors, histamine receptors,
α-adrenergic receptors
o binds covalently to all these receptors