Receptor Theories Flashcards
Prof. Akindele A.J.
Define the terms:
Intrinsic activity
Intrinsic efficacy
Affinity
Potency
Efficacy
Intrinsic activity: the ability of a drug to activate its receptor and produce a biological response. It is the relative maximal response caused by a drug in a tissue preparation
Intrinsic efficacy: a measure of biological effect produced per unit of drug-receptor complex formed
Affinity: the strength with which a drug binds to its receptor at any given moment or concentration.
Potency: the amount of drug needed to produce a specific biological response.
Efficacy: the ability of a drug to produce a pharmacological response once it binds to the receptor.
Define the terms:
Agonist
Partial Agonist
Inverse Agonist
Antagonist
Agonist: a drug or molecule that binds to a receptor and activates it to produce a biological response.
Examples: Morphine (opioid receptor agonist), epinephrine (adrenergic receptor agonist).
Partial Agonist: a drug that partially activates the receptor, producing a weaker response than a full agonist.
Example: Buspirone
Inverse Agonist: is a drug that reduces basal receptor activity. It has a negative efficacy, opposite to agonists.
Example: Rimonabant
Antagonist: a drug or molecule that binds to a receptor without activating it. It blocks the receptor from producing a response.
Examples: naloxone (opioid receptor antagonist).
Mention 4 types of receptors.
- Channel-linked receptors (Type 1/ionotropic receptors ) e.g. nAChR, GABAAR, Glutamate R etc.
- G-protein-coupled receptors (Type 2/metabotropic receptors) e.g. mAChR, adrenergic receptors, receptors for many hormones etc.
- Kinase-linked receptors (Type 3) e.g. receptors for insulin, cytokines and growth factors.
- Nuclear receptors (Type 4)- regulate gene transcription e.g. receptors for steroid hormones,
thyroid hormones, retinoic acid, vitamin D etc.
Mention 4 receptor theories.
- Occupancy theory
- Rate theory
- Operational Model
- Allosteric theory/Two-state theory
Discuss Occupancy Theory.
Receptor occupancy theory states that the effect of a drug (response) is proportional to the amount of receptors occupied by the drug.
Assumptions of occupancy theory:
1. The law of mass action applies
2. The response of the tissue is linearly related to receptor occupancy.
The law of mass action (LMA) states that the rate of a chemical reaction is proportional to the product of the active mass of the reactants.
LMA assumes that;
1. All receptors are equally accessible the specific ligand
2. Receptor-ligand binding is reversible
3. Receptors are either free or bound; there is no in-between.
4. Binding does not alter the receptor or ligand.
[A][R] <–K1——K2->[AR]
[A][R]/[AR] = K1/k2 = Kd
*Derive Hill-Languirs equation of fractional occupancy using 3rd assumption of LMA.
Θ = [A]/([A] + Kd)
Θ is PAR (fractional occupancy)
*Derive graph equation for Hill’s coefficient.
log(Θ/1-Θ) = log[A] - log(Kd)
–> log(y/100-y) = log[A] - log(Kd)
*Graphical representation
If equation holds, it should give a straight line graph with a slope of unity, and the value of the intercept of the line on the abscissa (i.e. at half Emaxl) would give an estimate of Kd.
*Limitations of the theory
For these reasons, other explanations have been sought beyond the simple models. Hence, concentration-response curves can often be described by the expression:
y = (ymax⋅[A]^nH)/ ([A]^nH50 +[A]^nH
where nH = Hill’s coefficient
y = obtained response
ymax = max response
What are the limitations of the Occupancy Theory?
- Hill’s coefficient (nH) is often >1 for responses mediated by ligand-gated ion channels
- Many tissues can attain maximal response with 1/10th occupancy of available receptors, rather than all the receptors
- When an agonist is applied at EC50, receptor occupancy can be as low as 1% instead of 50%
- Agonist concentration in the inner region of an isolated tissue may be much less than in the external solution, due to the presence of enzymes (e.g. cholinesterases) or uptake mechanisms (e.g. for noradrenaline)
Discuss Rate Theory.
The rate theory was developed by Paton WDM to explain experimental findings inconsistent with receptor occupancy theory.
Findings that could not be reconciled with occupancy theory included:
1. Observation of a block in receptor function after excitation by certain agonists (e.g. nicotine)
2. Trace stimulant action of certain antagonists and the persistence of this effect.
3. Effects of agonists demonstrated a fade with time.
The rate theory states that receptor excitation is proportional to the rate of drug-receptor interaction, rather than the number of receptors occupied.
Paton theorised that excitation resulted from the process of occupation itself, and that each drug-receptor association resulted in 1 quantum of excitation.
Comparing equilibrium effects obtained via Occupancy theory vs. Rate theory:
Occupancy theory:
y = ɸ´(x/[x + K2/K1])
Rate theory:
y = ɸ (K2⋅x /[x + K2/K1]
Where y = response recorded experimentally (mm),
ɸ´= constant that includes efficacy factor (e) of Stephen
x = concentration of drug added to the bath (g/mL),
K1 = association rate constant
K2 = dissociation rate constant
Rate theory predicts a fade to occur for all components in which K2 is not very large compared to k1x.
Discuss Allosteric Theory.
This is another theoretical framework adopted to describe quantitatively the general observation of non-linear coupling between receptor occupancy and response.
Monod, Wyman and Changeux proposed a model (MWC model) that could account for allosteric
phenomena in line with the following explanations about an allosteric system:
1. Allosteric proteins are oligomers; the protomers are associated such that they are functionally equivalent.
2. There is only one binding site for each ligand on each protomer.
3. The conformation of each protomer is constrained by its association with other protomers.
4. There are at least two states reversibly accessible to allosteric oligomers, described by the symbols R and T.
5. The affinity of one (or more) binding site towards its specific ligand is altered when a transition occurs from one state to another.
R<——-L—–>T
The R and T states are assumed to be in equilibrium in the absence of ligand, and the equilibrium constant for R T transition is denoted by L (allosteric constant)
An allosteric ligand (F) is one that possesses a different affinity for the two accessible states and thus displaces the equilibrium of the two states to a new equilibrium
favouring the state with higher affinity for F.
An example consistent with this model is the Nicotinic cholinergic receptor-mediated Na+ influx and
membrane depolarisation.
The cholinergic receptor was postulated to exist in 2 inter-convertible states: depolarised/active state(D) and a polarised or inactive state (P).
Agonists were postulated to have a higher affinity for the D state, and antagonists for the P state.
Antagonists would be predicted to shift the equilibrium towards the P state by preventing the shift to the D state, and partial agonists would have variable affinities for the two states but a preferential affinity for the D state.
Discuss the Operational Model.
- One theoretical shortcoming of the Occupancy theory is the ad-hoc nature of the efficacy term.
- The operational model eliminates the need for an empirical constant to account for efficacy
- This model is based on the premise that the efficacy term emerges from the relationship between receptor stimulation and observed response.
- The ligand-receptor complex (AR) activates response with a general equilibrium dissociation constant, Ke
Response/Emax = [AR]/[AR] + Ke
Substituting mass action for production of [AR] yields the equation for the operational model
Response = ([A]⋅[Rt]⋅Emax)/([A]⋅([Rt]+Ke) + [Ka × Ke])
where Rt = receptor density
KA = equilibrium dissociation constant of AR complex
Rt/ke = T
Thus, Response = ([AR]⋅T⋅Emax)/([A]⋅(T+1)+KA)
The tissue-specific component of T is the conc of [AR] that produces Emax. This value is maller for highly coupled tissues.
However, the nature of the agonist also matters because the more efficacious the agonist is, the smaller the amount of the receptor-agonist complex that is required to produce a response.
