Drug Receptor Theories Flashcards
What is affinity of a drug?
The tenacity at which a ligand binds to its receptor.
What is intrinsic activity?
The ability of a drug-receptor complex to produce a maximal result.
What is intrinsic efficacy?
The ability of a drug to elicit a response via single receptor
What is potency?
This is the how much of a drug is needed to produce a response
Affinity + zero efficacy = ?
Antagonist
Affinity + efficacy = ?
Agonist
Affinity + reverse efficacy = ?
Inverse agonist
Affinity + less efficacy = ?
Partial agonist
List the receptor theories according to the year in which they were postulated
Occupancy theory
Rate theory
Allosteric theory
Operational model
ORAO
List the receptor types/superfamilies
Channel-linked receptors (Type 1/ionotropic or ligand gated ion receptors)
G-protein coupled receptors (Type 2/metabotropic receptors)
Kinase-linked receptors (Type 3)
Nuclear receptors (Type 4)
List 3 kinase linked receptors
receptors for insulin, cytokines and many growth factors
List three types of channel-linked receptors
nACHR, GABA-R, glutamate
List three types of G-protein coupled receptors
mACR, adrenergic receptors, receptors for many hormones
What is the function of nuclear receptors?
Theyare for gene transcription
List 3 types of nuclear receptors
receptors for steroid hormones, retinoic acid, thyroid hormones, Vitamin D
Who postulated the occupancy theory and in what year?
Alfred Joseph Clark (1885 - 1941)
The receptor occupany theory proposed that dose-response relationships produced what kind of curve?
Hyperbolic curve
The receptor occupancy theory is based on the a study of the antagonism between?
Atropine and ACH in various muscle preparations
State the occupancy theory
Drugs combine with their receptors at a rate dependent of the concentration of both the drug and the receptor.
According to the occupancy theory, drug-receptor complexes breakdown at a rate proportional to the number of complexes formed. T or F?
True
In occupancy theory, drug-receptor interactions obey the principles of mass action. T or F?
True
In deriving Hill-Langmuir’s equation, what is the symbol and unit for the association rate constant?
K+1, M^-1s^-1
In deriving Hill-Langmuir’s equation, what is the symbol and unit for the dissociation rate constant?
K-1, s-1
What is the formula for proportion of free receptors?
Pr = [R]/[R]t = conc. of free receptors/conc. of bound receptors
What is the formula for the equilibrium dissociation constant?
Ka = K-1/K+2
Why is Pr + Par = 1
This is because according to theory, the binding site is either free or occupied
What is the Hill-Langmuir equation?
Par = [A]/Ka + [A]
What graphical illustrations can you plot based on the hill-langmuir equation
- Par vs [A]
- Par vs log [A]
Plot of log(Par/1-Par) vs log[A] should give what kind of graph and a slope of what?
The hill plot should give a straight line and a slope of 1 (unity)
There is a relationship between receptor occupancy and tissue response. T or F?
True
y/100 = Par. T or F?
True
y/100 = [A]/Ka + [A]. T or F?
True
How can the application of the expression, log(y/100 - y) = log [a] - log Ka, be tested and what will be the intercept on the x-axis?
By measuring a series of responses ( y) against different concentrations of A and then plotting the hill plot [log(y/100-y) vs log [A].
The intercept with be Ka.
List the criticisms of the occupancy theory.
- The hill coefficient is always greater then 1 in responses mediated by ligand-gate ion channels
- In many tissues, the maximal response (e.g the contraction of intestinal smooth muscle) by an agonist (ACh) is produced when >1/10th of the receptors are occupied as opposed to all of them as postulated by egn 3 (y/100 = Par)
- If an agonist is applied at a concentration required to give half maximal response ([A]50 or EC50), occupancy may be as little as 1% rather then 50% expected if response is directly related to occupancy.
- Many tissues contain enzymes or uptake mechanisms of which the agonists are substrates.
- Observation that excitation by certain agonists e.g nicotine, was followed by a block in receptor function.
- trace stimulant actions of certain antagonists and the persistence of these effects.
- Effects of agonists demonstrated a fade with time
Agonist conc. in the inner region of an isolated tissue may be much less than in the external solution. T or F?
True
A50 can sometimes be denoted as K. T or F?
True
State the rate theory
Excitation is proportional to the rate of drug-receptor interactions, not on the number of receptors occupied by the drug.
Who postulated the rate theory and in what year?
Paton WDM in 1961
The equlibrium effects obtained via occupancy theory can be expressed as?
Occupancy theory: y = O’(x/[x + K2/K1])
where y = response recorded experimentally (mm)
O: constant which includes efficacy factor of Stephenson
x: conc. of drug added to the bath (g/ml)
K1: association rate constant (s^-1g^-1ml)
k2: dissociation rate constant (s^-1)
The equlibrium effects obtained via rate theory can be expressed as?
Rate theory: y = O’(K2x/[x + K2/K1])
where y = response recorded experimentally (mm)
O: constant which includes efficacy factor of Stephenson
x: conc. of drug added to the bath (g/ml)
K1: association rate constant (s^-1g^-1ml)
k2: dissociation rate constant (s^-1)
What is the difference between the equilibrium effects obtained via rate theory and occupancy theory?
K2
Rate theory predicts a fade to occur in all compounds where K2 is not very large compared to K1x. T or F?
True
Under operational model, in terms of occupancy theory, a response to a ligand A is expressed as?
f[([A] x E[Rt]/[A] + Ka]
where E = intrinsic efficacy
[Rt] = receptor density
f = function that relates initial strength of activation (stimulus) to tissue response
Ka = equilibrium dissociation constant of the drug-receptor complex
In occupancy theory, drugs can be characterised with?
System-independent parameters like affinity and relative efficacy
One theoretical shortcoming of the Occupancy theory is the ad-hoc nature of the affinity term. T or F?
False.
One theoretical shortcoming of the Occupancy theory is the ad-hoc nature of the efficacy term.
The operational model was postulated by who and in what year?
Black and Leff in 1989
The operational model removed the need for an empirical constant to account for efficacy. Tor F?
True
The operational model is based on what premise?
The efficacy term emerges from an experimentally observed behaviour of pharmacological systems (the saturable relationship between receptor stimulation and the observed response)
According to the operational model, the relationship between receptor occupancy and response is often very hyperbolic in nature. T or F?
True
Response/Emax = [AR]/[AR] + Ke. What are Emax and Ke?
Emax = maximal response that can be obtained from the system
Ke = the concentration of the AR complex that produces 50% of the maximal response.
The more efficient the process is from the production of AR to response, the smaller the value of Ke. T or F?
True
Changes in the value of T leads to change in what?
responsiveness of the system to agonists
The constant used to characterise the propensity of a given system and a given agonist to yield a response is the ratio?
[Rt]/Ke denoted by T
T controls?
Potency of the agonist and the maximal response of the agonist
The conc. of agonist bound receptor that produces half the maximal tissue response is?
The tissue specific component of T
In highly coupled tissues, the tissue specific component of T will be large. T or F
False.
In highly coupled tissues, the tissue specific component of T will be small i.e small amount of receptor complex will produce a large response.
The more efficacious the agonist is, the smaller the amount of receptor-agonist complex that is required to produce a response. T or F?
True
Agonists will have a unique value of T for a given tissue. T or F?
True
The relationship between T values in one tissue will carry over to their relationship in other tissues. T or F?
True
Who postulated the allosteric theory and in what year?
Monod, Wyman and Changeux in 1965
Name a biological response consistent with the allosteric model.
Nicotinic cholinergic receptor-mediated Na+ influx and membrane depolarisation
What are the postulates of the allosteric theory?
- Allosteric proteins are oligomers; the protomers are associated such that they are functionally equivalent
- There is only one site for binding of each ligand on each protomer
- The conformation of each protomer is constrained by its association with other protomers
- There are at least two states reversibly accessible to allosteric oligomers, described by the symbols R and T
- The affinity of one or more binding site towards its specific ligand is altered when a transition occurs from one state to another.
