Potency of Agomelatine Vs Bupropion on Noradrenaline and Dopamine?

[JohnBoy2000]

From what I understand, Agomelatine has an effect as a result of a blockade on the 5HT2c receptor subtype, disinhibiting NA and DA release.
The Ki value associated with this antagonism is K_i=631nM.
Which, from my untrained eye, does not suggest a huge degree of potency.

Bupropion seemingly acts as a NA and DA reuptake inhibitor.

I couldn't find any information on its actual binding profile - cause wiki didn't have it.

Where else can I access binding profiles??

Anyways, I'm just comparing alternative noradrenergic AD's with Bupropion, and am curious about this particular comparison.

Anyone familiar with it?

The other potential option is Reboxetine, which has a NA reuptake binding value of Ki 13.4, which does appear quite potent, to my untrained eye.


The other curious point of consequence is that, the FDA did not license either of these for distribution in the US....?

 

[sekio]

Wiki does not always have binding affinities, usually they can be found in academic papers in places like PubMed. Ki is a measure of concentration and must have units attached to it, BTW. Saying a Ki of "13.4" means very little - do you mean 13 nM, 13 uM (= 13,000 nM) or 13 mM (= 13,000 uM = 13,000,000 nM) ?

You didn't look hard enough if you say wiki has no data on buproprion's binding

Here's a paper that compares receptor affinities of a whole bunch of antidepressants. Usually you can find binding information by searching for "[drug name] binding affinity ki" on Google. Also try Google Scholar and PubMed.

Buproprion is somewhat unique because it is a cathinone-type drug with affinity as a releasing agent at NET/DAT, most antidepressants are reuptake inhibitors only, or direct receptor agonists.

PS. Blockade of 5HT2c does a little more than alter NE/DA release too

 

[AlphaMethylPhenyl]

Bupropion continues to perplex.

Established: (mostly)NRI, DRI, NAC antagonist at some subunits

Not established: dopamine releaser, norepinphrine releaser, inhibition of dopamine release, inhibition of norepinephrine release

And yet it's an effective bipolar med, even as amp well-simulates mania?

I mean, I think that the latter two (inhibitors of release) are much more probable given its phenomenology. Perhaps a crucial part I'm missing is in regions activated. If it works in the hippocampus/frontal lobe almost exclusively...maybe some net result of nicotinic and DAT/NET interaction.

Shit made me stupid. I know that's taboo in this subforum (anecdotes), but I just have to say that, and its not all that an uncommon side effect. On the other hand, college kids gobble down adderall to work longer and put out more material. Maybe it's a stupid question, but I'm still perplexed.

Some part of the puzzle is clearly missing. I was hoping you could provide a more educated guess, sekio. Cheers.

 

[JohnBoy2000]

Wiki does not always have binding affinities, usually they can be found in academic papers in places like PubMed. Ki is a measure of concentration and must have units attached to it, BTW. Saying a Ki of "13.4" means very little - do you mean 13 nM, 13 uM (= 13,000 nM) or 13 mM (= 13,000 uM = 13,000,000 nM) ?

You didn't look hard enough if you say wiki has no data on buproprion's binding

Here's a paper that compares receptor affinities of a whole bunch of antidepressants. Usually you can find binding information by searching for "[drug name] binding affinity ki" on Google. Also try Google Scholar and PubMed.

Buproprion is somewhat unique because it is a cathinone-type drug with affinity as a releasing agent at NET/DAT, most antidepressants are reuptake inhibitors only, or direct receptor agonists.

PS. Blockade of 5HT2c does a little more than alter NE/DA release too

Super interesting first link.

How have I missed these things myself?

Probably a result of poor concentration ability/cognitive dysfunction.

But wow - lots to read, lots to learn.

Any more like that - let me have them!

 

[JohnBoy2000]

But yeah, that binding profile baffles me, as it claims that bupropion has very little potency on NA and DA.

The initial question still stands, in terms of agomelatines effect on NAT.
Potent, comparable to bupropion, or does it's main AD mechanism stem from melatonergic implications, and NET/DAT is only minor.

Reboxetine has a strong binding affinity for NE, but clinical trials claim that it's less efficacious than placebo...

 

[sekio]

Agomelatine is mostly a melatonin receptor agonist, I don't think it has any effects on norepinephrine transport.

 

[JohnBoy2000]

Agomelatine is mostly a melatonin receptor agonist, I don't think it has any effects on norepinephrine transport.

Really?

Well, that manufacturers are claiming it does.
As well as wikipeida, the NHS, multiple clinical trials...

As well as downregulation of 5-HT2c recepter subtype, inciting a release of NE and DA, no?

 

[sekio]

Agomelatine has literally 6,000x the affinity for melatonin receptors than it does to 5HT2C.... if there is an effect on NE release/reuptake etc it sure isn't direct.

 

[JohnBoy2000]

Agomelatine has literally 6,000x the affinity for melatonin receptors than it does to 5HT2C.... if there is an effect on NE release/reuptake etc it sure isn't direct.

Not necessarily disputing that but, that would infer that claims that it's a NA disinhibitor, is basically a marketing ploy??

I see fluxotine has a greater binding affinity for 5HT2c but, wikipedia tells me that really only comes into play at doses greater than 60mg.

You seem to be suggesting that any effect it has on NA and DA, would pale in comparison to Bupropions potency...?

 

[sekio]

You want a noradrenaline "disinhibitor", try something like yohimbine ! I suspect that it's a marketing label to call it a "disinhibitor" - it is apparently the only drug to be called as such. A little reminiscient of tianeptine being called a "SSRE" ... (turns out that it's an opioid... whoopsy)

Buproprion has direct activity at the norepinephrine/dopamine transporters, agomelatine doesn't. So yeah, buproprion has a larger effect on NE/DA levels.

 

[jaiho]

Agomelatine is a fairly weak anti depressant.
You'd be better off taking Nortriptyline, even instead of Bupropion.
It's stronger as an NRI & Dopamine disinhibitor via 5ht2c with potent binding.

 

[JohnBoy2000]

Agomelatine is a fairly weak anti depressant.
You'd be better off taking Nortriptyline, even instead of Bupropion.
It's stronger as an NRI & Dopamine disinhibitor via 5ht2c with potent binding.

Nortriptyline?
That has greater effect on NA/DA than bupropion?
From what I see, bupropions mechanism of action on NA does not involve indirect effects through serotonergic receptor subtype blockades.
I'm curious as to how a potency comparison between them could be made?

I understood that desipramine was the most potent tricyclic in terms of NA action?

 

[jaiho]

Nortriptyline?
That has greater effect on NA/DA than bupropion?
From what I see, bupropions mechanism of action on NA does not involve indirect effects through serotonergic receptor subtype blockades.
I'm curious as to how a potency comparison between them could be made?

I understood that desipramine was the most potent tricyclic in terms of NA action?

for DA, indirectly, yes. for NE, Nortriptyline is on par with desipramine, either will do the trick, though i have read in the literature that desipramine's effective dose is too close to it's toxicity dose.
Nortriptyline is a safe bet, cheap & readily available.
You'd just need to look at the binding profiles of each drug. I have not heard of Agomelatine working very well. Wellbutrin does not bind strongly to DA/NA transporters, so it's effectiveness is abit of a mystery. Considering it's also mentioned in the literature that Sertraline is a stronger DRI than Wellbutrin, and Sertraline only binds with a value of 300~ki to the dopamine transporter.

 

[JohnBoy2000]

The other thing to take into account with nortriptyline would be, its effects on mACH receptors.
Apparently less significant that first generation TCA's, but still pronounced.

It is reputed to induce sedation, as one of the foremost side effects, which does seem peculiar given that it is, I believe, licensed for treatment of chronic fatigue syndrome?

 

[adder]

^ Licensed? Are there any licensed drugs to treat chronic fatigue syndrome at all? If it's used for that purpose, then it's definitely an off-label use.

 

[JohnBoy2000]

Well, curious none the less as, like wiki says, sedation is one of its foremost side effects.

 

[jaiho]

It's quite a strong NRI. I find it only sedating at the start of treatment, as the H1 receptors downregulate, the NRI effect becomes more pronounced and its quite stimulating.
One of my favourite meds. I use it with an SSRI, and they synergise extremely well.
It's anti cholinergic side effects are the most mild of the TCAs as well, at least until you start getting higher with the dosages, then you might start getting dry mouth.

 

[JohnBoy2000]

Something to consider for future use at least.

The other thing of course is that, serotonergics make me drowsy - and my aim is to increase executive function.
NA and DA are most important in this, as was outlined in the "cognitive impairment" thread.

From what I see, nortriptyline does have a significant binding effect on serotonin. Not as much as NA, but quite prominent none the less.

Histamine downregulation with mirtazipine did not decrease with chronic use for myself; or the sedative effects of it, at least.

It's kind of a contradiction it would seem as, sedating in one sense due to histamine downregulation, but activating by it's NA effects.
Possibly sedating for myself due to its effect on serotonin.

 

[jaiho]

I also experience sedation from SSRIs in monotherapy. Hence why i wont consider an SSRI unless its augmented with something to increase energy.
But ive also tried Nortriptyline by itself for a few months. It has a robust anti depressant effect, but i found it wasn't enough to eliminate the disassocation & emotional numbness symptoms i have. I required an SSRI addition for that.

Mirtazapine is a far more potent anti histamine than Nortriptyline. Binding of Mirtazapine to H1 is 1-2nm~
Nortriptyline, it's 15nm.

In regards to the SRI properties of Nortriptyline, they aren't significant, even though the binding would make it seem that way. SERT binding is 16.5.
It has been combined with irreversible MAOIs, which would tell you that SERT binding isn't enough to cause serotonin syndrome, or significant enough to have a therapeutic effect.
Hence why adding an SSRI to Nortriptyline seems to cause a robust synergy. It starts to behave like a broad spectrum SNRI, more potent than Effexor, perhaps on par with California rocket fuel.

 

[JohnBoy2000]

Nortriptyline with mirtazipine - would that be an issue at all?

Mirtazipine has been like my, "base drug", whilst I augment the adjunct.
I love it.
Allows me to eat, sleep etc.

I'm getting the feeing 300 bupropion may be the max for myself cause, I'm pretty zombified on 450mg