Lecture 6 Flashcards
Concentration-response relations
the Clark model links occupation of a receptor by a molecule to a response
stickability = doability
molecules added to the bathing solutions attach to receptors, generate a response
once an equilibrium has been reached, the response seen at any given concentration plateaus
at each of those concentrations, the tendency of the molecule to sit on the receptor is balanced by its tendency to get off
when this happens, another molecule is waiting to take its spot
as the concentration increases, more and more molecules are jostling for the receptors, so that free receptors get fewer and fewer
when all receptors are potentially occupied, maximal response is obtained
the equilibrium that is obtained when 50% of the receptors are occupied provides an opportunity to estimate the affinity of the molecule for the receptor
Wrinkles in the Clark model
partial agonists = all receptors occupied, less than maximal response
spare receptors = partial occupation, full response
occupation and response are therefore not invariantly linked
Efficacy - a vexing issue
receptor plus a ligand are different entities
notion of an induced change - conformational induction
ligand produced conformational change when bound to receptor - induced doability
later notion emerged of a conformational selection
Malleability of proteins
proteins have many potential structures (conformations)
structure adopted is energetically favourable
multiple conformation exist at any given time
presence of other molecules/energy alters set of possible conformations
some conformations may be more active
constitutive activity = even under basal conditions, some conformations are coupled to intracellular processes
Activation of receptors
receptors can exist in two forms = inactive and active
frequency of receptors changes
Stochastic nature of the process
binding of a molecule to a protein is stochastic
essentially random, non-deterministic
at any moment, there will be a population of binding sites
which sites are bound will depend on the number of molecules that preferentially bind to that site
if the molecule has diffused away from that site, it becomes available for for other molecules similar (agonists) or dissimilar (antagonists)
Receptor equilibrium
full agonist partial agonist antagonist full inverse agonist inactive compound
Example of inverse agonism
histamine H3 receptors are inhibitory receptors
binding of histamine to these receptors leads to a decrease in release of neurotransmitters including histamine
less histamine in certain brain regions alters cognition and wakefulness
specific condition = narcolepsy
treatment to increase histamine at target sites
H3 receptor is constitutively active - under normal conditions, there is an inhibitory tone leading to a decrease of neurotransmitter release
an inverse agonist (pitolisant) will shift the equilibrium making the receptor less active and so reducing the inhibitory tone
Histamine at neurons
histaminergic neuron
non-histaminergic neuron
effector neuron
H1 = increased vigilance, increased attention, decreased feeding
H2 = increased working memory
NT receptor = increased cognition, increased sensory gating
NT = NE, ACH, 5HT, DA and others
Orthosteric interactions
the issue of antagonism
reversible/surmountable/competitive = will change potency, not efficacy since maximal response can still be obtained
irreversible/non-surmountable/non-competitive = will change efficacy since maximal responses cannot be obtained
Competitive antagonism
competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site of the receptor
response curves for the agonist are shifted to the right in a concentration-related manner by the antagonist such that the EC50 for the agonist increases with the concentration of the antagonist
if the antagonist binds to the same site as the agonist but does so irreversibly or pseudo-irreversibly (slow dissociation but no covalent bond), it causes a shift of the dose-response curve to the right, with further depression of the maximal response
Allosteric interactions
allosteric = the molecule binds to another site
two types of modulation possible
positive = enhances effects of agonists (potentiation)
negative = antagonize effects of agonists (antagonism)
more complex curves
probe dependence
Occurance of allosteric interactions
allosteric effects occur when an allosteric ligand I or P binds to a different site of the receptor to either inhibit (I) the response or potentiate (P) the response
this effect is saturable
inhibition or potentiation reaches a limiting value when the allosteric site is fully occupied
