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Confused about Ki Values of methylphenidate enantiomers

R

romealone

Bluelighter
Joined
Jan 28, 2010
Messages
112
Very confused on this...hoping someone can explain.
I know that Ki values refer to binding affinities, and the lower the Ki, the higher the affinity a drug has for a receptor/transporter.

When looking at Focalin (the D enantiomer of methylphenidate, which I know is about twice as potent as racemic methylphenidate, I see that the Ki value for the DAT is listed as 161, whereas the L enantiomer is 2250..obv a much lower affinity.

However, the racemic mixture of methylphenidate (Ritalin) which contains half dextro and half levo methylphenidate, the Ki value for the DAT is 121....meaning the racemic mixture has an even higher affinity for DAT than the isolated dextro enantiomer.

How is it possible that when you combine dextro (high affinity), with levo (low affinity), the final product ends up being something with a higher affinity than the isolated high affinity enantiomer.

If anything u would expect the affinity of the racemic mixture to fall somewhere in between the affinity of the high affinity dextro enantiomer and low affinity levo enantiomer, and yet somehow the affinity turns out to be greater than that of its highest affinity enantiomer.

It's like mixing chocolate and vanilla ice cream and the result being a nice cream that is darker brown than chocolate itself.

What am I missing
 
Mightttt wanna post this in the advanced drug discussion. People may know here but that shit just flew right over my head.
 
Where'd you get this data? Perhaps they're taking the dissociation constant(Ki) of peripheral DA Transporters when they talk about the binding affinity of racemic methylphenidate?
 
What am I missing
Click to expand...

I saw this too, a long time ago, scratched my head over it and then figured it's either measurement error, typo, or a new mode of binding. Either that or they're doing it in cell culture that breaks down the D-enantiomer.

The measurements of Ki values do have an error figure associated with them, maybe you should check that.

It could also be the case that pairs of D and L enantiomers both bind to DAT at once with a higher affinity than either alone.

It's also worth noting that tighter binding doesn't necessarily mean a drug is going to be more effective in vivo. For instance I have read that the (edit: L-enantiomer) of methylphenidate is rapidly destroyed and doesn't make it to the blood in significant levels when administered orally.

OD --> NSPD
 
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sekio said:
I saw this too, a long time ago, scratched my head over it and then figured it's either measurement error, typo, or a new mode of binding. Either that or they're doing it in cell culture that breaks down the D-enantiomer.

The measurements of Ki values do have an error figure associated with them, maybe you should check that.

It could also be the case that pairs of D and L enantiomers both bind to DAT at once with a higher affinity than either alone.

It's also worth noting that tighter binding doesn't necessarily mean a drug is going to be more effective in vivo. For instance I have read that the D-enantiomer of methylphenidate is rapidly destroyed and doesn't make it to the blood in significant levels when administered orally.

OD --> NSPD
Click to expand...

I understand your points and appreciate your trying to offer some logical explanation that addresses this mystery, but it still doesn't sit right with me.

To make matters more confusing, consider the values for NET. The D enantiomer of MPH has a Ki value of 206 for NET whereas the isolated L enantiomer has an extremely low affinity (High Ki) of >10,000 for NET (the norepinephrine transporter). However, once again, the racemic mixture of MPH has a Ki of 51 for NET. This case is even more bizarre because one would think the addition of the EXTREMELY low affinity L enantiomer to the R enantiomer would significantly lower the affinity of the racemic when compared to the relatively high affinity D enantiomer. But once again, the racemic mixture actually has a HIGHER affinity (Ki of 51) for NET compared to the D enantiomer's Ki of 206.

Regarding your suggestion that isolated D enantiomer of MPH is destroyed rapidly in vivo and does not reach significant concentration in the blood, unless I am misunderstanding, that makes little sense to me as the isolated D enantiomer of EPH is Focalin, which is well known to be approximately twice as potent as racemic MPH (Ritalin)
 
Regarding your suggestion that isolated D enantiomer of MPH is destroyed rapidly in vivo and does not reach significant concentration in the blood, unless I am misunderstanding, that makes little sense to me as the isolated D enantiomer of EPH is Focalin, which is well known to be approximately twice as potent as racemic MPH (Ritalin)
Click to expand...

Oopsy, I mean the L-enantiomer.
 
I'm not sure how the binding assays were conducted, but use of an inappropriate radioligand can yield weird affinity (Ki) values for DAT. If the values don't make sense than the most likely explaination is that they are erroneous.

I don't see any weird issues with the values in the following publication:

http://online.liebertpub.com/doi/abs/10.1089/cap.2006.16.687

Uptake inhibition, IC50

DA:
d-MPH = 0.19 uM
dl-MPH = 0.26 uM
l-MPH = 1.8 uM

NE:
d-MPH = 0.034 uM
dl-MPH = 0.052 uM
l-MPH = 0.47 uM
 
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