L3 - The concept of antagonism Flashcards
describe competitive antagonism
binding site: molecules compete for the receptor binding site based on relative conc. and affinity
nature of binding: bind reversibly to agonist binding site, without activation, to inhibit agonist binding
effect on agonist dose-response: a rightward shift in agonist dose-effect curve (without decreasing max response)
- more agonist is required to produce the max response
example of competitive antagonist
cetirizine is a competitive antagonist for histamine receptors
describe irreversible antagonist
binding site: molecule covalently bonds to receptor preventing agonist binding and activation, permanently unresponsive
nature of binding: bind irreversibly to agonist binding site, effectively reducing functional RT
effect on dose-response curve: a rightward and downward effect on the curve
- due to a decrease in active receptors
example of irreversible antagonist
phenoxybenzamine (PBZ) forms a covalent bond with the agonist binding site on the a-adrenoceptor, preventing agonist (e.g. adrenaline) binding to the receptor
used to treat pheochromocytoma a tumour-induced hyperproduction of adrenaline in glands preoperatively to tumor removal
It is not commonly used because it lacks selectivity for alpha ADR and binds MSR
describe allosteric antagonist
Binding site: have their own binding site on the receptor that is distinct from the binding site for the endogenous agonist.
Nature of binding: a conformational change in the receptor which, in turn, reduces the affinity and/or efficacy of the agonist. NON-competitive. Allosteric antagonists affect E and A differently.
How do allosteric modulators decrease agonist affinity
NAM binding to the allosteric binding site changes the agonist binding site, reducing affinity of the agonist for its binding site.
Increased agonist conc. can overcome NAM
How do NAMs affect the dose-response curve in terms of affinity
a rightward shift is observed but limited by a ceiling effect
- ceiling effect occurs due to the saturation of allosteric modulators
How do allosteric modulators decrease efficacy
NAMs can bind to allosteric sites to affect: 1. receptor activation 2. downstream signalling, and 3. maximum response without changing the orthosteric site
How do NAMs affect the dose-response curve in terms of efficacy
Limited reduction in the maximum response of an agonist is viewed, this response is saturable as allosteric sites are filled.
This antagonist turns a full agonist into a partial agonist
example of an allosteric antagonist
Maraviroc
- decreases the affinity of HIV-1 (gp120) for CCR5 and decrease viral entry
describe functional antagonism
involves ligands acting at different receptors to produce opposing effects within the same cell, both are agonists
example of functional antagonism
Functional antagonism is used to treat anaphylactic reactions, high histamine release causes SM contraction in the airways, this is opposed by adrenaline that relaxes SM and allows are easier breathing
Dose-response curve visualisation of functional antagonism
dose-dependent but limited antagonism because receptors (for both agonists) can be saturated (fully occupied)
This response is relative
describe inverse agonism
Inverse agonist selectively binds to & stabilises the inactive receptor conformation, moving the equilibrium away from the constitutively active conformation – decreasing constitutively active receptors, reducing cellular effect.
How is inverse agonism represented on a dose-response curve
an inverse agonist selectively binds to
& dose-dependently stabilises the inactive conformation (Ri) of the constitutively active receptor
- this is shown as a - value of log [drug]
