Receptor Theory 2 Flashcards
What does the occupancy equation predict from a full agonist?
that the concentration required to produce 80% of the max response will be 16x greater than the concentration required to produce 20% of the max response
How does Stephensons model allow for two drugs to act as full agonists without having the same efficacy?
Based on the idea that 10 arbitrary units is a max response…different potencies and efficacies can result in a max response
i.e. f= 50% and efficacy = 20 200.5 = 10
f=10% and efficacy = 100 0.1100 = 10
Prove that the minimum efficacy for a full agonist would be 10
agonist would require to occupy the whole receptor population as 10*1.0 = 10
Why are EC50 and Kd concentrations not identical when spare receptors are involved?
Kd is the agonist concentration where 50% of the total receptor population is occupied
If an agonist only requires 10% on the population to elicit 50% of the maximal response then Kd and EC50 will be different
What is the equation representing the agonist fractional occupancy in the presence of a reversible competitive antagonist?
E/Emax = [D]/[D]+Kd(1+[a]/Kant)
What type of graph is shown with a reversible competitive antagonist?
rectangular hyperbola shifted to the right
How does the presence of a reversible competitive antagonist represent on a double reciprocal plot?
no change in y-axis but new x-axis intercept
How can the dose ratio be used in a Schild plot to determine Kant?
D2/D1, D3/D1, D4/D1 plotted will show a straight line slope of 1 and the x-axis intercept gives log Kant
What is the pA2 value?
a numerically simplified way of indicating the antagonist dissociation constant
Give an example of a reversible non-competitive antagonist
Ketamine non-competively inhibits NMDA glutamate receptor
Give an example of an indirect antagonist
Nifedipine blocks VGCC that noradrenaline activates through a-adrenoceptors
How is the agonist fractional occupancy in the presence of a non-competitive antagonist represented?
E/Emax = [D]/([D]+Kd)(1+[A]/Kant)
What is the effect of the non-competitive antagonist on a concentration response curve?
same Kd but different Emax
What is the effect of the non-competitive antagonist on a double reciprocal plot?
change in y-intercept but not x-intercept
What are the two possible scenarios for allosteric effects producing non-competitive antagonism?
antagonist has no effect on agonist binding but changes receptor conformation to prevent agonist from activating response
conformational change decreases strength of agonist binding or prevents binding
Given an example of a non-competitive allosteric antagonist acting on mAChRs
Gallamine
Give an example of an allosteric antagonist that regulates enzyme action
d-tubocurarine inhibits acetylcholinesterase metabolism of ACh
Give an example of an irreversible competitive antagonism
Naloxone for mu-opioid receptor antagonists as forms a covalent bond
What is the effect of irreversible competitive antagonism on Emax and Kd?
Emax is reduced
Kd is the same as agonist binds free receptors
What is an inverse agonist?
an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist
What is cooperativity?
displayed by some receptors and enzymes that have multiple binding sites where the affinity for a ligand is increased or decreased upon the binding of a ligand to a site
What is homotropic cooperativity?
when the molecule causing the cooperativity is the one that will be affected
what is heterotropic cooperativity?
where a third substance causes the change in affinity - allosteric cooperativity
How is the general relationship for co-operativity shown?
E= Emax[D]^n/[D]^n +Kd
What kind of graphs are produced by positive and negative cooperativity?
n>1 for positive creates sigmoidal
n
What is the equation for cooperativity also known as?
the Hill Equation
How can the equation be changed around to represent the equation of a straight line?
log10(E/Emax-E) = nlog10[D] - log10 Kd
Why is it useful that hill plots can give values for n that are not whole numbers?
indicates strongly whether there is cooperativity or multiple receptor populations as receptors can’t bind a fraction of a drug
What is an advantage of using an allosteric modulator as a therapeutic target?
they have not undergone the same evolutionary stresses to accommodate an endogenous ligand so offer greater GPCR selectivity
Why do allosteric modulators have less potential for toxic effects?
they have a ceiling level of effects irrespective at the administered dose
What is an advantage of allosteric modulators not expressing appreciable efficacy?
it has the ability to selectively tune up or down tissue responses only when the endogenous agonist is present
