Buxton: receptor theory Flashcards
main targets of drugs (4)
think TIER
- -enzymes (aspirin, cyclooxygenase)
- -transporters/carriers (prozac, serotonin reuptake transporter)
- -ion channels (local anesthetics + Na+ channels)
- -receptor proteins (cimethidine for histadine receptor)
(drug, target)
“receptor”
PROTEIN that participates in cellular communicatin via chemical signals
ligand
chemical signaling molecule that transmits signal to biochemical change in target
ligand examples (just throw a few out there)
drugs or hormones and NT
Receptor theory equation
D + R –> DR —> Effect
drug, receptor, drug-receptor complex
mass action
rate of RXN proportional to the product of concentration of reactants
JUST THINK LE CHATERLIER’S
hill langmuir equationa
[D] + [R] [DR]
k1=forward rxn
k-1= reverse rxn
Radioreceptor/radioligand binding assay
[receptor prep + radiolabeled drug + test drug] get put into test tube. then placed into a drug receptor complex, filtrated, and unbound drug or unbound radiolabeled drug get eluted off.
PURPOSE: figure out Kd/KA
kinetic experiment (radiolabeled)
look at K1 and K2 over time by looking at specific binding (counter per minute). K1 in mol/sec. k2 in sec.
total binding line
specific binding + non specific binding binding curves. add areas under curves
specific binding line
it’s linear and strong but then it tapers off, kinda looks the the Vmax line
non specific binding
binding to places OTHER than the THERAPEUTIC target. This line is linear so directly propertional to ligand added
Hyperbolic concentration binding curve
Drug concentration binding curve (x-axis) vs fraction of receptor bound [B] y axis.
Kd=when half of the receptors are bound (same thing as Ka)
Bmax = just Kmax but for binding (rectangular hyperbola).
Scatchard plot
specific binding/ free radioligand (y axis) vs specific binding (x axis).
B max is the x intercept
slope = -1/Kd
if specific binding, then LINEAR line
Hill-Langmuir equation
Background just to help out: Kd= k-1/k1; it’s a concentration. also known as dissociation constant.
Par = [D][[D] + Kd]]
where AR = DR
SUPER LEGIT TO FIGURE OUT PROPORTION OF DR/AR
log linear scale
y axis; fraction of receptor bound, B.
x axis: concentration in log scale.
overall: graph sigmoidal, and it’s easy to see the Kd; this means that drug is acting well
ED50
TD50
LD50
therapeutic effect (dose) toxic effect (dose) lethal (dose) at which 50 percent of ppl are affected
What’s the difference between graded concentration response curves and hyperbolic concentration binding curve?
y axis: %maximal response v fraction of bound
graded concentration response curve similarities to binding curve?
x axis: concentration in same units
GRAPH shape rectangular hyperbola in both
Quantal dose response curve
describe pop % responding rather than individual responses. in log scale and helps us identify best dosage
Full Agonist: two cases
max potency and MAX EFFECT
other case, reduced potency but MAX EFFECT
Partial Agonist
max potency but REDUCED EFFECT.
other casse, reduced potency but REDUCED effect
Potency
deterimined by concentration needed for effect
What determines whether or not something is a full or partial agonist?
If the effect% is close to 100, then it’s full.
If effect% is low (close to 50%), then it’s partial
Chemical antagonists
two drugs in solution that cancel each other out
Physiological antagonists
two drugs that cancel each other out physiologically, like histamine and epinephrine
Pharmacological antagonists
Blockade of one DRUG RECEPTOR (but do not activate transduction cascade) by another compound, like propanolol blocking norepinephrine. Prevent agonist (drugs or hormones) from acting.
Where do competitive antagonists bind?
they bind to same site on receptor as agonists!
How can competitive antagonists be overcome?
by increasing agonist concentration, so it’s reversible
Do competitive antagonists mainly affect potency or efficacy?
potency!
Which are more clinically useful? Competitive or non competitive antagonists?
Competitive antagonists!!!
Where do non-competitive antagonists bind?
They bind covalently and irreversibly to the agonist binding site OR to a site different to the agonist (reversibly or irreversibly)
Can non-competitive antagonist inhibition be overcome by increasing agonist concentration?
NOPE coz we can’t get the agonist to compete for the same site
Do non competitive antagonists mainly affect potency or efficacy?
Efficacy!!!
concentration/dose response curves
Effect% v D:
linear scale: rectangular hyperbola
log-linear: totally sigmoidal; shows drug is acting well!
Spare receptors appear commonly in the receptors for what ligands?
in receptors for hormones or NT
ED50, TD50, LD50
concentrations at which half of individuals :
ED–have therapeutic effect
TD–have toxic effect
LD–have lethal effect
Spare Receptors
pool of available receptors»_space; # required for full response
Explain spare receptor effect in relation to concentrations of D, R, and DR.
Sooo [R] goes up coz you got a greater pool of receptors; therefore, you don’t need as much [D] to reach same [DR] concentration!
What’s the net effect of spare receptors?
Increased sensitivity to ligands
What changes occur on the [D] vs receptor occupancy happen due to spare receptors?
Potency increases; so (ED50) value becomes smaller, but the max value of effect percentage is the same!
Does response % increase linearly with receptor occupancy % WITHOUT spare receptors?
Yup. so biological effect is proportional to [DR] at all drug concentrations
Does response % increase linearly with receptor occupancy % WITH spare receptors?
Biological effect is proportional to biological response % only in low concentrations up to ED50… HOWEVER it continues as a hyperbolic rectangle thereafter.
How does effect of drug change when drug is given continuously or repeatedly?
It’s effect usually diminshies
What’s tachiphylaxis?
A sudden decrease in response to drug after administration
What causes receptor mediated drug desensitization? (2)
- loss of receptor FXN.
2. loss of receptor #
What causes non-receptor mediated drug desensitization? (3)
- reduction of receptor-coupled signaling components.
- reduction of [Drug]
- physiological adaptation
What’s the cause to lose receptor FXN and lose sensitivity?
and is this rapid or slow?
- due to change in receptor CONFORMATION (like phosphorylation of Gprotein receptors).
- usually part of cellular feedback mechanism
it’s a RAPID desensitization!
What’s the cause to lose receptor NUMBER and then lose sensitivity?
and is this rapid or slow desensitization?
- usually due to feedback effects of cell on agonist.
- example: phosphorylation removes GPCR from cell surface.
IT’S LONG TERM!!!
Therapeutic window
The relation of [Drug] to their therapeutic effects to and adverse effects in a population
Full agonist
Drug can go two ways: Rinactive or Ractive. it chooses the active route and, therefore, increases response level!
Partial agonist
Drug goes mainly to Ractive and, TO A LESSER EXTENT, Rinactive, so response level decreases a bit from partial agolist
Inactive compound
Basal activity or drug goes to RI and Ra at same rate
Inverse agonist
Drug goes to Ri and then level of response decreases a lot
Do receptors mainly express the constitutive system or the native one?
Constitutive seems to be more important.
Receptor antagonists FXN?
They DO NOT provoke a response in receptor cells; HOWEVER, they dampen the agonist activity.
Agonist examples (prolly don’t need to know well)
- Losartan for Hypertension
- bisperidone for antipsychotic
- -famotidine for hyperaciditicty
