Drug Targets Flashcards
What is efficacy?
The ability to create a signal by binding to a receptor. Drugs with zero efficacy block receptors when they bind
What is selectivity?
Preferential binding to certain subtypes leads to a greater effect at that subtype than others. Lack of selectivity can lead to unwanted effects
Ionotropic receptors
Very fast (ms) Binding of agonist causes conformational change in receptor too
G-protein coupled receptors
fast (s)
beta alpha and gamma units stuck together. When inactive they have GDP when active bind to GTP and alpha subunit goes off by self
What are Gi Gq and Gs?
Gi = inhibitory Gs = Stimulatory Gq = reacts with phospholipase C (to facilitate SMC contraction)
Gi and Gs can be bidirecitonal so different receptors can exert opposing effects on the target enzyme
Catalytic recpetors
Minutes/days
Growth factors and hormones
receptors usually trigger a kinase cascade
What are two important Catalytic pathways?
Ras/Raf/MAp kinase - cell differentiation
Jak/Stat - inflammation
Intracellular recpetors
hours/days long lasting steriod hormones Always invovle changes in gene transcription Bind to DNA needs to be lipid soluable
What is EC50?
the measure of agaonist potency. The lower the EC50 the greater the potency
What is pD2?
The -ve log of EC50
What is pA2?
-ve log of the concentration that shifts the curve two-fold
Competitive reversible antagonism
competes directly with the agonist for binding to the receptor
Parallel rightwards shift of the curve
What is the equation for Pa2?
pA2x + log(x-1)
x = EC50 (presence of agonist)/EC50(absence of agonist) pAx = -ve log conc (M) of the antagonist
Competitive Irreversible Antagonism
Competes directly with the agonist for binding but binds with greater affinity (normally convalantly)
Causes a non parallel rightward shift of the concentration response curve (depresssion in the maximal response)
What is pD2’
Potency measure of irreversible antagonism and non competitive antagonism
A measure of how good and antagonist is at depressing the curve
What is the Spare receptor theory?
Agonist does not have to bind to all receptors to cause a response so there is enough for antagonist to bind and you still get a good response
Non competitive antagonism
Interfere with the signal pathway
do not bind to same receptor as against
on parallel rightward shift and depression in maximal response
pD2’
Physiological antagonism
Occurs when two agonists working at different receptors have opposing actions
e.g histamine causing bronchoconstriciton
adrenaline causing bronchodilation
Partial agonists
Do not elicit a maximal resposne so the ir efficacy is less than 1.
Can act as antagonists to full agonists
Crossover on the conc response curve as they can help initially
Inverse angonists
Some receptors are naturally active and inverse agonists will turn the receptors off
Receptor Plasticity (regulation of receptors)
Changes in receptor state
Exhaustion of mediators
Changes in receptor population
Receptor state changes
Rapid pronounced desensitisation of metabotropic receptors due to phosphorylation
Heterologus - one agonist desensitizes a completely different agonist. Often invovles protein kinase A/C
Receptor population changes
Chronic agonist administration can lead to down regulation. Continued desentitisation leads to cell removing receptors from membrane.
Chronic antagonist administration can lead to upregulation as cell sends out more receptors to ‘find’ agonist
The clinical effects of population changes in tricyclic antidepressents
the therapeutic effect fo theses takes 2-4 weeks as cell starts to down regulate receptors in response to increased dopamine so therefore there is no obvious change
Enzymes as targets
e.g COX for inflammation and ACE for hypertension
COX 2 selective inhibitors
Are selective to only inhibit COX 2 not COX1 so don’t lead to GI problems
Drugs which interact with carrier proteins
e.g drugs that act on monoamine NT uptake protein to take monoamines back into pre synaptic neuron such as Fluoxetine as an antidepressant
