Partial Agonists and Inverse Agonists Flashcards
What is the deal Castillo-Katz mechanism
AR -(E)-> AR*
The agonist binding encouragesthe receptor to form an active conformation ( critical step) this ability is called efficacy
How does receptor activation occur
This happens through bond formation between A and R, A makes new bond with R and this encourages R to close up and stay in this active conformation
Why is it easier for a Receptor to reach its active state when a Agonist is bound.
This is because the transition from R to R* has a large energy demand and this puts strain on the bonds/ interactions in the receptor, therefore its not obtainable. But with an agonist bound makes the AR* state a much lower energy state which is much easier to achieve and only a small “kick” is needed to reach the resting state again. Thus A can alter this free energy landscape making it more energetically favorable for a receptor to assume its active conformation making it possible to activate
What happens if we change the agonist slightly?
◎ I.e delete one of the charges, step 1 is unchanged I.e. binding, however, in the next step where we encourage the receptor to close up, now we only have one charge to attract the 2 in the receptor, and when the receptor is closed or in its active conformation I’ve only got one charge holding it their thus expecting the rate at which we move forward , the attraction is weakened, and the rate is slower and the holding time on average will be less because less bonds are holding the, together and thus it will come out of this state quicker back to the resting state- partial agonist
What if we go further with changes the agonist completely?
The molecule will compete for the agonist binding site but it just blocks the actual agonist, it does not produce any response. It can still bind to the agonist but it doesn’t inhibit nor activate it, a competitive reversible antagonist, the active complex is energetically unfavorable
What happens with constitutively active receptors?
It’s a receptor that can assume it is in the active conformation without being bound to an agonist- lower activity, inverse agonist
What is meant by spare capacity
It is when you have a pool of receptors (more than you need)
How can we dictate the difference between a full and partial agonist?
A full agonist produces 2 units of activity if it occupies 2 receptors
Whereas, a partial agonist will produce 2 units of activity if it occupies 8 receptors- efficacy is lower
What is the Gaddis equation-representing reversible competitive antagonism
PAR= conc.A / Ka(1 + conc.B/Kb) + concA
What is the dose ratio and what is its equation
It’s the concentration ratio of A that gives the same level of response with 2 different conc. of antagonist (B)
r= con.A with more B / conc of A with zero B
The Schild equation
r = 1 +[B]/Kb
And this is how we test for a true competitive antagonist
The schild equation applies if…
A) the antagonist is a true competitive antagonist( not a partial or inverse agonist)
B) at every binding site, the binding of A and B is mutually exclusive
C) The value of Kb is the same at every binding site
D) when there is the same level of occupancy of Athe response is always the same
E) the system is at equilibrium
To check if the schild equation is obeyed we..
Plot a straight line by re-arranging the equation and taking logs of both sides.
