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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 7 of 7. This is the beginning of the thread.
Posted by Optimist on January 24, 2005, at 18:58:38
I've been looking at the K values given for different test ligands of specific drugs and am having trouble understanding their meaning.
For example Tranylcypromine(Parnate) had a K value of >10,000(nM) at the Dopamine D2 receptor.
d-amphetamine has a K value of >10,000 as well for the Dopamine D2 receptor.
Bromocriptine has a K value of 2...
Bupropion(Wellbutrin) has a K value of >100,000...
Olanzapine(Zyprexa) has a K value of 31...
So I'm a little confused on what the K value means. Does a higher number mean more dopamine being bound to the post-synaptic D2 receptor, or vice versa? Or is it something totally different?
Also what does the dopamine transporter mean? Is it the amount of dopamine released from the presynaptic terminal?
As well what is the clinical significance of these values? Do they predict any specific treatment response?
Thanks guys,
Brian
Posted by fachad on January 25, 2005, at 0:14:41
In reply to PDSP K values Database help, posted by Optimist on January 24, 2005, at 18:58:38
I think the strengh of a drug's binding to a ligand is 1/K, so the lower the number, the more potent the drug.
examples:
K is 200 -- 1/200 = 0.0005
K is 3 -- 1/3 = 0.3333
Posted by SLS on January 25, 2005, at 6:29:35
In reply to Re: PDSP K values Database help, posted by fachad on January 25, 2005, at 0:14:41
> I think the strengh of a drug's binding to a ligand is 1/K, so the lower the number, the more potent the drug.
>
> examples:
>
> K is 200 -- 1/200 = 0.0005
> K is 3 -- 1/3 = 0.3333
This website displays the Ki of a great many ligands to various receptors - even transporters.
- Scott
Posted by SLS on January 25, 2005, at 6:30:05
In reply to Re: PDSP K values Database help, posted by SLS on January 25, 2005, at 6:29:35
> > I think the strengh of a drug's binding to a ligand is 1/K, so the lower the number, the more potent the drug.
> >
> > examples:
> >
> > K is 200 -- 1/200 = 0.0005
> > K is 3 -- 1/3 = 0.3333
>
>
> This website displays the Ki of a great many ligands to various receptors - even transporters.
>
>
> - Scott
http://kidb.bioc.cwru.edu/pdsp.php
Sorry....
Posted by Larry Hoover on January 25, 2005, at 8:50:04
In reply to PDSP K values Database help, posted by Optimist on January 24, 2005, at 18:58:38
> I've been looking at the K values given for different test ligands of specific drugs and am having trouble understanding their meaning.
Just so everyone's on the same page, this is in reference to the database at: http://kidb.cwru.edu/pdsp.php
> For example Tranylcypromine(Parnate) had a K value of >10,000(nM) at the Dopamine D2 receptor.
>
> d-amphetamine has a K value of >10,000 as well for the Dopamine D2 receptor.
>
> Bromocriptine has a K value of 2...
>
> Bupropion(Wellbutrin) has a K value of >100,000...
>
> Olanzapine(Zyprexa) has a K value of 31...
>
> So I'm a little confused on what the K value means. Does a higher number mean more dopamine being bound to the post-synaptic D2 receptor, or vice versa? Or is it something totally different?The Ki is the concentration [in nM (nanomolar), which is crudely parts per billion] at which the test ligand (the drug being considered) binds to the particular receptor *compared to* the binding of the hot ligand (some other drug, or the natural ligand), such that it occupies 50% of the receptors.
It is important, therefore, to find data which are most reflective of the natural human brain. You would get a more reasonable estimate of Ki if the receptor type (headings Species and Source) are 'human' and 'cloned', respectively. Moreover, where possible, make sure that the Hot Ligand is the radioactive form of the natural ligand. That would be represented as e.g. 3H-dopamine. That's radioactive hydrogen (tritium) substituted for natural hydrogen on the dopamine, allowing it to be "counted" accurately. If the drug displaces dopamine from its receptor (at a known receptor concentration), the radioactivity diminishes, allowing them to calculate the 50% occupancy value (taken off a graph, by the way, so it is always an estimate).
There's more to consider, though. Binding itself is only part of the effect of a drug. This table tells you nothing about the effect of the drug when it is bound to the receptor.
After it binds, the drug might do nothing. That makes it a pure antagonist. It's like somebody parking in your parking spot. You can't use it. Or, the drug could stimulate the receptor just as if the natural ligand was present. That is agonism. Agonism comes in many flavours. A partial agonist does some stimulating, but not as much as the natural ligand. A full agonist is equivalent in stimulation. You can also have agonists that exceed the stimulating effect of the natural ligand (at the same concentration). And, bizarre as it may sound, it could also be a reverse agonist. A reverse agonist has the opposite effect of the natural ligand.
To further complicate matters, some drugs have differing levels of agonism, depending on their own concentration. In other words, non-linear response to dose.
The hyperlinked references in the right-most column will take you to Pubmed, and a good part of the time, there will be information about the agonism/antagonism issue. If not, you have to try and find out the old-fashioned way (search).
> Also what does the dopamine transporter mean? Is it the amount of dopamine released from the presynaptic terminal?
The dopamine transporter is the pre-synaptic reuptake pump. It recycles dopamine for later use, and removes it from the synapse rapidly. Anything that inhibits it does two things. It exaggerates the effect of the dopamine that was released, and it reduces the amount of dopamine available for later release.
It is the dopamine transporter that is hit by d-amphetamine, for example.
> As well what is the clinical significance of these values? Do they predict any specific treatment response?
>
> Thanks guys,
>
> BrianYes, they predict treatment response, but only in the context of the agonism/antagonism process. We also have to know something about what the receptor does in the first place.
A high affinity (low Ki; values in single digits as an example) ligand will always substantially displace the natural ligand, even at very low concentrations. Drugs with lower affinities (high Ki) will have to be taken in stronger doses to have a similar effect. Then, if it is an antagonist, it will have an effect similar to down-regulation of the receptor. If it an agonist, however, it stimulates the receptor even in the absence of the normal ligand. That is analogous to up-regulation, and/or activation of the receptor. You need both parts of the relationship to predict the clinical effect of the drug.
And, just to add another conditional element to these considerations.....we know that there are genetic differences in the chemical makeup of the different receptors and transporters. If you've got a mutation in *your* receptors, this information may not apply at all.
Yet another consideration is the metabolic transformation of the drug. The effects of the parent drug often are quite different from the metabolites (some of which are very active themselves).
Lar
Posted by Optimist on January 25, 2005, at 10:13:49
In reply to Re: PDSP K values Database help » Optimist, posted by Larry Hoover on January 25, 2005, at 8:50:04
> > I've been looking at the K values given for different test ligands of specific drugs and am having trouble understanding their meaning.
>
> Just so everyone's on the same page, this is in reference to the database at: http://kidb.cwru.edu/pdsp.php
>
> > For example Tranylcypromine(Parnate) had a K value of >10,000(nM) at the Dopamine D2 receptor.
> >
> > d-amphetamine has a K value of >10,000 as well for the Dopamine D2 receptor.
> >
> > Bromocriptine has a K value of 2...
> >
> > Bupropion(Wellbutrin) has a K value of >100,000...
> >
> > Olanzapine(Zyprexa) has a K value of 31...
> >
> > So I'm a little confused on what the K value means. Does a higher number mean more dopamine being bound to the post-synaptic D2 receptor, or vice versa? Or is it something totally different?
>
> The Ki is the concentration [in nM (nanomolar), which is crudely parts per billion] at which the test ligand (the drug being considered) binds to the particular receptor *compared to* the binding of the hot ligand (some other drug, or the natural ligand), such that it occupies 50% of the receptors.
>
> It is important, therefore, to find data which are most reflective of the natural human brain. You would get a more reasonable estimate of Ki if the receptor type (headings Species and Source) are 'human' and 'cloned', respectively. Moreover, where possible, make sure that the Hot Ligand is the radioactive form of the natural ligand. That would be represented as e.g. 3H-dopamine. That's radioactive hydrogen (tritium) substituted for natural hydrogen on the dopamine, allowing it to be "counted" accurately. If the drug displaces dopamine from its receptor (at a known receptor concentration), the radioactivity diminishes, allowing them to calculate the 50% occupancy value (taken off a graph, by the way, so it is always an estimate).
>
> There's more to consider, though. Binding itself is only part of the effect of a drug. This table tells you nothing about the effect of the drug when it is bound to the receptor.
>
> After it binds, the drug might do nothing. That makes it a pure antagonist. It's like somebody parking in your parking spot. You can't use it. Or, the drug could stimulate the receptor just as if the natural ligand was present. That is agonism. Agonism comes in many flavours. A partial agonist does some stimulating, but not as much as the natural ligand. A full agonist is equivalent in stimulation. You can also have agonists that exceed the stimulating effect of the natural ligand (at the same concentration). And, bizarre as it may sound, it could also be a reverse agonist. A reverse agonist has the opposite effect of the natural ligand.
>
> To further complicate matters, some drugs have differing levels of agonism, depending on their own concentration. In other words, non-linear response to dose.
>
> The hyperlinked references in the right-most column will take you to Pubmed, and a good part of the time, there will be information about the agonism/antagonism issue. If not, you have to try and find out the old-fashioned way (search).
>
> > Also what does the dopamine transporter mean? Is it the amount of dopamine released from the presynaptic terminal?
>
> The dopamine transporter is the pre-synaptic reuptake pump. It recycles dopamine for later use, and removes it from the synapse rapidly. Anything that inhibits it does two things. It exaggerates the effect of the dopamine that was released, and it reduces the amount of dopamine available for later release.
>
> It is the dopamine transporter that is hit by d-amphetamine, for example.
>
> > As well what is the clinical significance of these values? Do they predict any specific treatment response?
> >
> > Thanks guys,
> >
> > Brian
>
> Yes, they predict treatment response, but only in the context of the agonism/antagonism process. We also have to know something about what the receptor does in the first place.
>
> A high affinity (low Ki; values in single digits as an example) ligand will always substantially displace the natural ligand, even at very low concentrations. Drugs with lower affinities (high Ki) will have to be taken in stronger doses to have a similar effect. Then, if it is an antagonist, it will have an effect similar to down-regulation of the receptor. If it an agonist, however, it stimulates the receptor even in the absence of the normal ligand. That is analogous to up-regulation, and/or activation of the receptor. You need both parts of the relationship to predict the clinical effect of the drug.
>
> And, just to add another conditional element to these considerations.....we know that there are genetic differences in the chemical makeup of the different receptors and transporters. If you've got a mutation in *your* receptors, this information may not apply at all.
>
> Yet another consideration is the metabolic transformation of the drug. The effects of the parent drug often are quite different from the metabolites (some of which are very active themselves).
>
> Lar
>
>
Wow, thanks Larry. I really appreciate the time you spent answering my questions.I've taken a neuropsychopharmacology course at university so I understand many of the mechanisms you have outlined.
Yeah I forgot to post the website for what I was talking about. Thanks for the help.
I was basically trying to see how Parnate compared to other prodopaminergic drugs, and some AP's to see the contrast. I'll have to sort through all the data now to see what I can find. Once again, you've been a great help!
Brian
Posted by Optimist on January 25, 2005, at 12:36:53
In reply to Re: PDSP K values Database help » Optimist, posted by Larry Hoover on January 25, 2005, at 8:50:04
I've looked through the data and realized I can't really compare Parnate to dopamine agonists, amphetamines, and reuptake inhibitors.
Since Parnate doesn't bind to any presynaptic/postsynaptic receptors it doesn't give any relevant data. Dopamine release isn't measured either from the amphetamines and Wellbutrin so it's probably not the best tool for comparing these drugs.
Larry, would you have any other resources to compare dopamine activity with respect to the amount that's in the synaptic gap perhaps, or some other mechanism?
Thanks
Brian
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