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19 Cards in this Set
- Front
- Back
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To re-cap The binding of a drug to a receptor is... |
• Governed by binding affinity. • Quantified in terms of KD, the concentration of drug required to occupy 50% of the receptors at equilibrium. |
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the activation of a receptor is... |
• Governed by efficacy, the ability of drugs to activate the receptor once bound.
• Difficult to quantify.
• Drug action described in terms of high (full agonist), low (partial agonist) or zero (competitive antagonist) efficacy. |
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There are a number of ways to measure affinity of a drug for a receptor. One method is... |
radioligand binding assays |
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describe radioligand binding assays... |
• Consider the situation where we want to measure the affinity of a new drug, “relaxin” at cannabinoid receptors in the brain. How might we do this? • A common method is to label the drug with a radioactive isotope (eg 3H or 32P) • This allows us to detect and measure the amount of drug bound in tissue samples • We can gain information on the number of specific binding sites (cannabinoid receptors) in our tissue (brain) and the affinity of the drug (relaxin), for these sites. |
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Using radioligand binding assays we can find out the Bmax and Kd... |
maximum number of receptors per tissue (Bmax) and the affinity (KD) of the radiolabelled drug (see lecture slides for full details) |
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re cap some points on reversible competitive antagonists... |
• Very important drugs e.g. pancuronium, terfenadine, propranolol • Used to inhibit the effects of a neurotransmitter or hormone • Their effects can be overcome by increasing the concentration of the AGONIST i.e. the blockade is surmountable |
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Reversible competitive antagonists produce a parallel shift to the right of the AGONIST log concentration vs response curve true or false? |
true |
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Antagonist affinity can be measured by... |
The extent to which the agonist curve is shifted by the antagonist is a measure of the affinity of the ANTAGONIST for the receptor The shift can be measured using the “dose-ratio” i.e. the ratio of the concentration of agonist producing the same response in the presence and absence of the antagonist. |
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For a reversible competitive antagonist, the dose ratio should increase linearly with the concentration of the antagonist. true or false? |
true |
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The affinity of a reversible competitive antagonist is quantified using its pA2. Define pA2... |
This is the negative logarithm of the concentration of antagonist that necessitates that you double the agonist concentration to produce the same response (i.e. dose ratio = 2.0) |
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An example... • The presence of 6.3 x10-9 M propranolol necessitates that you need to double the concentration of noradrenaline to produce the same increase in heart rate. The calculation is therefore... |
• The log of 6.3 x10-9 is -8.2 • The pA2 for propranolol is 8.2 |
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Obtaining the pA2 by experiment... |
• Construct (log)concentration response curves for the agonist in the presence of several concentrations of antagonist • This allows the pA2 to be calculated by “Schild analysis” • Moreover, it allows the experimenter to determine whether the antagonism is competitive • Construct (log)concentration response curves for the agonist in the presence of several concentrations of antagonist • This allows the pA2 to be calculated by “Schild analysis” • Moreover, it allows the experimenter to determine whether the antagonism is competitiv |
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The Schild equation is... |
log (dose ratio -1) = log (antagonist concentration) – log KB • KB is the dissociation equilibrium constant (similar to KD) for an antagonist |
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• For a reversible competitive antagonist a plot of log (dose ratio-1) versus log antagonist concentration (a Schild plot) should have a slope of 1.0 and intercept the X-axis at (log KB). true or false? |
true |
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for a reversible competitive antagonist how what is the equation to calculate pA2? |
• For a reversible competitive antagonist pA2 = pKB = -logKB |
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Steps in producing a Schild plot (1)... |
• Construct (log)concentration-response curves to the agonist in the presence of several concentrations of antagonist • From the curves read the the logEC50 values (from the x axis) for the agonist in the absence and presence of the different concentrations of antagonist • Calculate the EC50 values for the agonist in the absence and presence of the different concentrations of antagonist |
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Steps in producing a Schild plot (2)... |
• Calculate the dose ratio for each concentration of antagonist
An example EC50 in absence of antagonist = 1.5 x 10-7 M EC50 in presence of antagonist = 6.0 x 10-7 M Dose ratio = (6.0 x 10-7)/(1.5 x 10-7) = 4.0 Plot Log (dose ratio-1) versus Log [antagonist] |
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If the slope of the Schild plot does not equal 1.0, (or at least fall in the range 0.8 to 1.2) what does this suggest? |
It suggests that the antagonism is NOT competitive or NOT reversible |
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Is the pA2 obtained for the antagonist dependent or independent of the agonist used? |
Independent • Note that the pA2 obtained for the antagonist is independent of the agonist used as it is a measure of antagonist affinity for the receptor • Often receptors are characterised by the pA2 values calculated for different antagonists acting on them |
