Receptor theory Flashcards
What is a drug
A chemical substance that is able to change the physiological function of the organism
Name macromolecular drug targets
Enzymes Transporter proteins Ion channel proteins Receptors (cell surface or intracellular) Nucleic acids
What is drug specificity
Refers to the different chemical structure/shape of a drug dictating the ability to bind/induce a response
What are the two main models proposed for drug-receptor binding
Lock and key
Zipper
Describe the lock and key model for drug-receptor binding
Receptor = lock; Agonist = key
Only holds up if the receptor/ligand have a specific, unchanging shape
Describe the zipper model for drug-receptor binding
Drug molecule is flexible, binds to receptor in stages.
Occurs in some cases, but not every drug does this
Give examples of bonds involved in drug-macromolecular binding
Covalent
Ionic
Hydrogen
Van der waals
Discuss covalent bonds in the context of drug-macromolecular binding
Strongest
Irreversible
Can be useful for drugs to form because gives longer lasting effects (but can be bad if bad side effects). Not used for agonists
Discuss ionic bonds in the context of drug-macromolecular binding
Strength varies. Stronger in hydrophobic environments.
Drugs stored in ionised salt states.
Important function groups - COOH, NH2, SH, phosphate (ionised at pH 7.4)
What assumptions are the single occupancy theory based on
A measured biological response (E) is proportional to fractional occupancy (not the case with partial agonists)
The drug is not degraded by the system
Effect is seen by 1 drug molecule binding to 1 receptor molecule
Effect is measured when reaction has reached equilibrium
Define agonist
A molecule that is able to bind to a receptor and induce a response
Define partial agonist
As an agonist, but produces a sub-maximal effect
Define intrinsic activity
The ability for a drug to produce an effect after binding
Define spare receptor
Only a certain proportion of receptors need to be occupied to produce a maximal response. All others are Spare Receptors.
How is intrinsic activity linked to the simple occupancy theory
Agonists and partial agonists have different intrinsic activity (f). Simple occupancy theory does not account for this so was adapted.
What is the simple ‘occupancy theory’
Binding of a drug to an appropriate receptor/binding site is reversible, and extent determined by following the reversible equilibrium:
D + R DR
(forward rate = K1; the association rate constant)
(backward rate = K2; the dissociation rate constant)
What is the criteria for hormone-receptor mediated events
Receptor must:
have structural/steric specificity for hormone
be saturable/limited
cell specific hormone/receptor binding
Have high affinity for the ligand at physiological concentrations
Once ligand binds to receptor a chemical event must occur
If pH = pKa what is the degree of ionisation
50%
Name major properties of receptors
Recognition (of ligand)
Saturability (finite no.)
Reversibility (non-covalent binding - H bonds etc)
Steroeoselectivity (only recognising one optical isomer)
Agonist specificity (structurally similar drugs should bind well)
What shape is a log dose-response curve
Sigmoidal
What is an EC50 value
The effective concentration of agonist needed to produce 50% of maximum response
When the simple occupancy theory is accurate, what value is equal to EC50
Kd
What type of agonist is not explained by the simple occupancy theory
Partial agonists.
How is intrinsic activity measured
intrinsic activity = f.
Full agonists = 1
Antagonists = 0
Partial agonists > 0 and < 1
How does a dose/response curve look different if there are spare receptors present
Much steeper increase as lower dose needed to produce Emax.
Who incorporated ‘spare receptors’ into the occupancy theory
Stephenson.
Which two factors is the size of the stimulus thought to depend on
Agonist fractional occupancy (spare receptor) Agonist efficacy (e)
Describe how the efficacy of agonists can vary
Some agonists produce a varied response even when occupying the same number of receptors
Contrast high- and lower- efficacy agonists
High - max resp while occupying low proportion of receptors
Low - Cannot activate to the same degree, can behave as partial agonists.
Define ‘super agonists’
Efficacy greater than the endogenous agonist
Define ‘silent antagonist’
Has affinity but no efficacy
State the % Efficacy of different types of ligand
Super agonist >100
Full agonist =100
Partial agonist 0
How can two different full agonists generate the same Emax with different efficacies
Different combinations of efficacies/spare receptor properties can give the same stimulus (Emax)
What is the minimum efficacy required for an agonist to be ‘full’
10 (arb units). This would require occupancy of whole receptor population.
How does Emax/occupancy relate to EC50
If Emax is reached at a lower occupancy, EC50 will be lower (and vice versa)
What does drug potency depend on
Kd and efficacy
What happens when an antagonist binds to a receptor
Agonist binding/ transduction systems prevented
No activation of response
What shape is a concentration-response curve
Rectangular hyperbolic
What happens to the concentration-response curve in the presence of a competitive antagonist
Increased concentration needed to produce same response. Unchanged Emax
What happens to the log concentration-response curve in the presence of a competitive antagonist
Both sigmoidal. Antagonist produces parallel shift to the right. Increased log concentrations needed. Unchanged Emax.
How does a double reciprocal plot change when competitive antagonist is added
New straight line produced. Different x-axis intercept. Unchanged y-axis intercept
What are dose ratios
Agonist concentrations needed to produce a given level of response in the absence/presence of increasing conc of antagonist
What does a Schild Plot show
The relationship between the different dose ratios (Dr) and its corresponding antagonist concentration.
What should a Schild Plot look like when from made from a competitive antagonist dose ratio
Slope = 1. Positive increase.
What is the pA2 value
A value used to simply indicate the antagonist dissociation constant
Give an example of a non-competitive antagonist
Ketamine. Antagonist of the NMDA glutamate receptor.
Nifedipine. Antagonist of VGCCs.
Define indirect antagonism
Antagonist that binds to a site on a downstream signalling component that has no physical association with the agonist binding receptor.
What happens to the concentration-response curve in the presence of a NON-competitive antagonist
Reduced Emax. EC50 unchanged.
What happens to the log concentration-response curve in the presence of a competitive antagonist
Reduced Emax. EC50 unchanged
How does a double reciprocal plot change when a NON-competitive antagonist is added
New line:
X-axis intercept unchanged
Y-axis intercept changed
How does a reversible non-competitive antagonist affect the dose-response curve
Decreased Emax
EC50 unchanged
Give an example of an irreversible competitive antagonist
Naloxazone. Mu-opioid receptor antagonist.
How can some irreversible antagonists act like non-competitive antagonists
Can initially bind quickly and reversibly to the receptor. Covalent bonds form later.
Seems like non-comp initially.
Name an inverse agonists
Beta-carboline. Acts on the benzodiazepine binding site on the GABAa receptor.
Name an agonist, inverse agonist and antagonist of the GABAa receptor
Agonist: Diazepam
Inverse Agonist: Beta-carboline
Antagonist: Flumazenil
Describe the two state model
GPCRs may exist in two states.
R - no Gs coupling. No cAMP.
R* - GS coupling. cAMP.
Some (not many) receptors exist as R* receptors
Describe the two state model in the context of agonists, inverse agonists and ‘pure’ antagonists
Agonists: Prefer R* state
Inverse agonists: Prefer R state
‘Pure’ Antagonists: no effect on equilibrium of R/R*
What is cooperativity in the context of receptors
Some receptors have multiple binding sites where the affinity of the binding sites for a ligand is in/decreased upon binding of a ligand to a binding site.
Name the two types of cooperativity (receptors)
Homotropic cooperativity
Heterotropic cooperativity
Define homotropic cooperativity
When the molecule causing the cooperativity is the one that will be affected by it
Define heterotropic cooperativity
Where a third substance causes the change in affinity (allosteric)
Name some benefits of using allosteric modulators instead of orthosteric modulators
GPCR allosteric binding sites are not as conserved, so more selective.
Decreased potential for toxic effects.
If has little efficacy, can slightly in/decrease tissue response in presence of endogenous agonist.
