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Re: more modafinil perplexities

Posted by SLS on April 21, 2006, at 7:50:35

In reply to more modafinil perplexities, posted by zeugma on April 20, 2006, at 23:07:45

> I suppose I deserve what I get at this bleary-eyed hour for me. But I've been reading about modafinil-based hybrids for some time, and then I read what has to be the most surprising abstract in some time:
> Bioorg Med Chem Lett. 2006 Apr 16; [Epub ahead of print]
> Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors.
> Musachio JL, Hong J, Ichise M, Seneca N, Brown AK, Liow JS, Halldin C, Innis RB, Pike VW, He R, Zhou J, Kozikowski AP.
> Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346, 10 Center Drive, Bethesda, MD 20892-1003, USA.
> (11)C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([(11)C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([(11)C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [(11)C]5 and [(11)C]6 display high affinity for the NET in vitro (K(i)=0.94 and 0.68nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.
> I am pretty ignorant of chemistry and structure-activity relationships and the like. But this last sentence surprised me as much as it must have the investigators.
> -z

That's interesting. However, binding to a transporter does not guarantee that it will act as a reuptake inhibitor. Mazindol is an example of this at the DAT.

What do you feel is the significance of this study? It is incredible how they can now design drugs and predict their biological activity.

Do you think such a hybrid would be helpful in the treatment of depression? What about in your situation?

I am amazed that there is still so much uncertainty regarding the mechanism(s) of action of modafinil.

NE alpha-1 activation
DAT inhibition
glutamate release
hypocretin release

I thought the first two had been disproved.

- Scott




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