Psycho-Babble Medication Thread 635435

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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

 

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

 

Re: more modafinil perplexities SLS

Posted by zeugma on April 22, 2006, at 20:51:40

In reply to Re: more modafinil perplexities, posted by SLS on April 21, 2006, at 7:50:35


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.>>

If I am not mistaken mazindol is sometimes used as a ligand for the NET. Has mazindol been researched in depression?


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

I have gotten what seems to be an antidepressant effect from provigil at times. It is difficult to isolate a given drug's effect when taking multiple psychotropics. But certainly, from the binding profile alone of the hybrid (subnamolar potency at the NET; nanomolar potency at the DAT) it might be useful as a stimulating AD.

>>
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
>>

There is a researcher at NYU named Stone, who claims to have observed a partial agonist effect of modafinil at alpha-1B receptors. but he admits that his observations are provisional. He is doing extensive research on alpha-1 receptors in depression. He focuses especially on the role that epinephrine, as distinct from NE, plays in the etiology of depressive states.

on the other hand, a study of DAT knockout rodents found that these animals were insensitive to the stimulating effects of modafinil and methamphetamine, but were normally responsive to the locomotor stimulating effects of caffeine. They took this to imply that modafinil in fact gets its effects from the DAT.

It is interesting that both Stone and the researchers who conducted the studies on modafinil and DAT KO animals concede that modafinil is a low-affinity ligand at each receptor, but still gets significant behavioral effects. The studies on modafinil and glutamate/GABA are convincing, but there is no mechanism yet observed to account for its effects on amino acid transmission. OTOH, a direct effect was observed on modafinil's effect on the preoptic area (inhibition of NE reuptake), so this must be a region-specific effect- modafinil's affinity for the NET is much lower than its weak affinty for the DAT. And yet the effect was quite convincing:

Sleep. 2004 Feb 1;27(1):19-25.


Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.

Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P.

UMR 5167 CNRS, Physio-Pathologie des Reseaux Neuronaux du Cycle Veille-Sommeil, Institut Federatif des Neurosciences de Lyon (IFNL, IFR19), Universite Claude Bernard Lyon I, Lyon, France.

STUDY OBJECTIVES: The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. MEASUREMENTS AND RESULTS: Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. CONCLUSIONS: These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.


I find modafinil to be much unlike either Ritalin or conventional NET inhibitors. Perhaps its effect is most similar to that of Cylert, which itself has a poorly defined mechanism of action.

-z

 

Re: more modafinil perplexities zeugma

Posted by ed_uk on April 23, 2006, at 10:23:47

In reply to Re: more modafinil perplexities SLS, posted by zeugma on April 22, 2006, at 20:51:40

Zeugma, you are so intelligent it's almost scary!!! :)

Ed

 

Re: more modafinil perplexities

Posted by SLS on April 23, 2006, at 10:47:49

In reply to Re: more modafinil perplexities SLS, posted by zeugma on April 22, 2006, at 20:51:40

> > 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.

> If I am not mistaken mazindol is sometimes used as a ligand for the NET.

I haven't really seen it used that way. However, I think it probably does produce NET inhibition elsewhere in the body. Although Mazindol does suppress appetite, its main effect is probably lipolytic resulting from the activation of NE receptors in brown adipose tissue. I guess its use as a test ligand depends on which area of the brain is being assayed. I see on Medline that Mazindol is still used to determine DAT density. It wouldn't be of much use if it weren't selective unless one were to use it regionally.

> Has mazindol been researched in depression?

I think it was originally investigated as one. It's too bad that it doesn't act as a DA reuptake inhibitor. A sister drug, ciclazindol, was also looked at. I don't know why it wasn't pursued. It seemed to be safe and effective.

> I have gotten what seems to be an antidepressant effect from provigil at times. It is difficult to isolate a given drug's effect when taking multiple psychotropics. But certainly, from the binding profile alone of the hybrid (subnamolar potency at the NET; nanomolar potency at the DAT) it might be useful as a stimulating AD.

That would be great!

> > 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

I guess the more recent literature has disproved the disproved.

> There is a researcher at NYU named Stone, who claims to have observed a partial agonist effect of modafinil at alpha-1B receptors. but he admits that his observations are provisional. He is doing extensive research on alpha-1 receptors in depression. He focuses especially on the role that epinephrine, as distinct from NE, plays in the etiology of depressive states.
>
> on the other hand, a study of DAT knockout rodents found that these animals were insensitive to the stimulating effects of modafinil and methamphetamine, but were normally responsive to the locomotor stimulating effects of caffeine. They took this to imply that modafinil in fact gets its effects from the DAT.

Methamphetamine needs the DAT to enter the cell so as to produce a release of neurotransmitter. Does this mean that modafinil produces a release of DA? I don't know how the brain evolves without DAT. I guess if the postsynaptic membrane grows to be more sensitive to DA stimulation, I can see how modafinil would have an activating effect as a DAT inhibitor.

> It is interesting that both Stone and the researchers who conducted the studies on modafinil and DAT KO animals concede that modafinil is a low-affinity ligand at each receptor,

Which receptors? DAT and NET? I guess you mean the binding sites on the transporters. Still receptors, I know.

> but still gets significant behavioral effects.

I know. You sometimes have to ask how small an effect must be before it can be considered negligible. Low-affinity might still be high enough. I guess it is pretentious to declare anything negligible without proving it in vivo.

> The studies on modafinil and glutamate/GABA are convincing, but there is no mechanism yet observed to account for its effects on amino acid transmission. OTOH, a direct effect was observed on modafinil's effect on the preoptic area (inhibition of NE reuptake), so this must be a region-specific effect- modafinil's affinity for the NET is much lower than its weak affinty for the DAT. And yet the effect was quite convincing:
>
> Sleep. 2004 Feb 1;27(1):19-25.
>
>
> Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.
>
> Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P.
>
> UMR 5167 CNRS, Physio-Pathologie des Reseaux Neuronaux du Cycle Veille-Sommeil, Institut Federatif des Neurosciences de Lyon (IFNL, IFR19), Universite Claude Bernard Lyon I, Lyon, France.
>
> STUDY OBJECTIVES: The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. MEASUREMENTS AND RESULTS: Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. CONCLUSIONS: These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.
>
>
> I find modafinil to be much unlike either Ritalin or conventional NET inhibitors. Perhaps its effect is most similar to that of Cylert, which itself has a poorly defined mechanism of action.

Years ago, Cylert was thought to work via a passive diffusion of DA across the membrane as opposed to an active vesicular release. It's too bad about the liver thing. It would still be nice to have around.


- Scott


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