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Why are melatonin receptor agonists being developed as antidepressants?

Its also available here in Switzerland starting this year...

I'm curious on that potential metabolite 7-Methoxi-1-naphtylethylamin and if it has any action on the monoaminergic system resp. binds to other 5-HT receptors, contributing to Agomelatins activity. We know that 2-NAP is a monoaminereleaser and PIHKAL proved that many of the corresponding 2C's are active as well (the closest is 2C-G-N), so what can one expect from 7-Methoxi-1-naphtylethylamin?
 
Extremely interesting stuff on Tianeptine... of course, the only thing more of a mystery than its mode of action is why this stuff hasn't yet become *the* antidepressant of choice, and why other companies don't seem to be too interested in developing their own Tianeptine copycat, instead trying to mess around with the noradrenergic system to produce ineffective, side effect ridden garbage like Reboxetine.

Agomelatine (Valdoxan) has already been avalailable in my location for a few months now, and I'm probably going to give it a try once the public health insurance will cover it.
 
Hodor said:
Extremely interesting stuff on Tianeptine... of course, the only thing more of a mystery than its mode of action is why this stuff hasn't yet become *the* antidepressant of choice, and why other companies don't seem to be too interested in developing their own Tianeptine copycat, instead trying to mess around with the noradrenergic system to produce ineffective, side effect ridden garbage like Reboxetine.
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Your comment implies that tianeptine is remarkably effective. I've surveyed Bluelight for reliable personal reports on tianeptine and they vary enormously. Some are overwhelmed, some underwhelmed, and many (most?) are just whelmed.
 
They will verify? I don't think so. If they haven't been conducted, they won't be.



Frankly, it wasn't possible for there to be a big series of copycats. Very few derivatives maintained similar activity, and they were all included in one patent.
 
I was just researching another melrag, tasimelteon, and found that its maker, Vanda, is developing a stim (VSF-173). Longshot, but does anyone know what this looks like? Here's some info:

NSFW:
VSF-173 is an orally administered stimulant. The exact mechanism of action is unknown. It is under investigation by Vanda for the treatment of excessive sleepiness. In preclinical studies, VSF-173 demonstrated effects on animal sleep/wake patterns and gene expression suggestive of a stimulant.

In April of 2007 Vanda initiated a phase II trial of VSF-173 for the treatment of excessive sleepiness. This randomized, double-blind, placebo-controlled trial planned to enroll 60 healthy subjects who were to receive three oral doses of VSF-173 or placebo. The primary endpoint of the trial was the difference from placebo on the Maintenance of Wakefulness Test (MWT).

In October of 2007 Vanda released positive results from a phase II trial of VSF-173 for the treatment of excessives sleepiness. This randomized, double-blind, placebo-controlled trial enrolled fifty-five subjects who received three doses of VSF-173 administered at 50 mg, 100 mg and 200 mg and placebo administered at 25 mg, 50 mg and 100 mg at the usual bedtime and at four hours after the first dose. Efficacy was measured via a series of six Maintenance of Wakefulness Tests (MWT) given two hours apart starting one hour after the first dose, as well as the scheduled daytime recovery sleep following the night time and morning evaluations. Although not statistically significant, VSF-173 demonstrated improvement over placebo on the primary endpoint, the effect of the compound on the first four series of MWT tests. The mean MWT sleep onset scores for the 50 mg, 100 mg and 200 mg, and placebo groups were 10.3, 12.9, 10.6 and 9.2 minutes, respectively. In a subset of 37 subjects with no observed impairment in pre-dose daytime wakefulness, the mean of all six MWT scores for the 50 mg, 100 mg and 200 mg groups showed improvements of 2.1, 3.4 and 2.1 minutes, respectively, compared to placebo. For the dose group of 100 mg, this observation of improvement was statistically significant (p < 0.05). During the scheduled daytime recovery sleep, statistically significant, dose-dependent correlations were observed with the following polysomnography (PSG) parameters: increased number of awakenings, decreased sleep efficiency and total sleep time for the first third of the sleep period, and increased wake time after sleep onset for the first 3 hours of the sleep period (p<.05). Based on the results, Vanada planned to move forward with the development of VSF-173.

VSF-173 was licensed to Vanda Pharmaceuticals by Novartis in January of 2006. Under the terms Novartis retained an option to commercialize the product on its own after phase II and phase III trials.
 
Sorry I didn't post what I intended too. Just have no time for me at all since sometime now.

At least, I'll let you know a few things that more than a year of Agomelatine trials in our forum taught us (edit: the numbers are only subjectives. We, unfortunately, didn't poll or collect data.) :

1. (Spoiler Alert!) Ironically, Agomelatine induces insomnia in around 1/3 of the users. It reduces the sleep time uncomfortably by around ~2 hours in around 1/3 of the users and is only really beneficial for the sleep quality of the last 1/3. Very few people at neutral at that level. The insomnia is obviously caused by the sensitivity of some people to the increased frontal adrenergic stimulation that provide 5-HT2c antagonism. The melatonin agonism doesn't compensate enough in those individuals. About 1/3 of the people quitting Agomelatine does so because of sleep related disturbance.

2. Agomelatine doesn't seem, to me, to generate an higher response rate than Fluoxetine and al, but it feels way more natural. When it works, people usually reports feeling genuinely good/happy without any feeling of being on a drug.

3. There's a world of difference between 25mg and 50mg. More than twice the beneficial effects, with much side effects increase. Except for the insomnia\reduced sleep time, which prohibit many to stay on the 50mg.

4. Sexual side effects are so subtle that you can't even be 100% sure you aren't imagining them (try second guessing yourself on Paroxetine...).

5. About 25% of the users reports slight anxiety rebound in the afternoon.

6. The poop out rates seems about 1/3 lower than with SSRIs, but happens.

7. Hypomania happens. Probably about as often with Agomelatine as with Fluoxetine. 5-HT2c antagonists are known to do that.

8. Agomelatine seems to be good enough to be considered as first choice antidepressant. Starting on 25mg is good Mild depression (per BDI2 standard) while I feel 50mg should be considered, without the need for titration, for Moderate depression. I would recommend Agomelatine - alone - for severe depression, but 50mg in smart polypharmacy is sure better than any SRIs.

9. There's virtually no withdrawal symptoms, but it very rarely happens and those are quite weak.

10. For non insomnia susceptible individual suffering from dysthymia, Agomelatine is great and I predict Agomelatine a lot of success in that niche when it gets in the US. Wellbutrin will suffer from the competition for sure.

11. Agomelatine isn't a great anxiolytic and is likely somewhere between Wellbutrin and most SRIs. It's worth noting that while SRIs tend to loose their anxiolytic with time, Agomelatine's anxiolytic builds up with time. Agomelatine could be more anxiolytic than SRIs if taken long term. Some reports -slightly- reduced social anxiety (and increased sociability). (Social Phobics, it doesn't warrant any excitation about it.)

12. See #13

13. Don't be fooled by Agomelatine short half-life. The magic in the day is even better than the one during the night while you get the 5-HT2c antagonism and melatonergic treatment. Also, while it feels good when you take it at bed time, it's hardly enjoyable to have it in your blood during daytime anyway.

14. Agomelatine is easy to obtain. Just follow the white rabbit in my last post and ask the mad hats when you get there.


/\/\
 
Good post WMarty.

I personally do think that ago would work for social anxiety, SSRI's arent really effective either in this regard.
 
You miss the point, but regardless, in that list of studies you provide, the obvious thing that is noticed is that it's not exactly without side effects. In one, there are identical withdrawals.
 
WMarty said:
I would recommend Agomelatine - alone - for severe depression, but 50mg in smart polypharmacy is sure better than any SRIs.
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would = wouldn't?

For non insomnia susceptible individual suffering from dysthymia, Agomelatine is great and I predict Agomelatine a lot of success in that niche when it gets in the US. Wellbutrin will suffer from the competition for sure.
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Very interesting. Thanks for the great post!
 
Why is it that at Wikipedia, under Melatonergics:catabolism there's a big list of MAO inhibitors?

melatonin isn't a monoamine, and it isn't metabolised by MAO. makes no sense at all.
 
Clearly not a monoamine. But this brings us back to my question from the other day about that potential metabolite of Agomelatin which IS a monoamine:

hugo24 said:
I'm curious on that potential metabolite 7-Methoxi-1-naphtylethylamin and if it has any action on the monoaminergic system resp. binds to other 5-HT receptors, contributing to Agomelatins activity....
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rocknroll714 said:
What are you smoking? It is a monoamine and it is metabolized by MAO, just like serotonin:

Selective inhibition of MAO-A but not MAO-B activity increases rat pineal melatonin.
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People wonder why I'm an asshole all the time, but then you see moronic comments like this where people say retarded things like "[melatonin] is a monoamine" or "it is metabolized by MAO, just like serotonin" and then go on to quote studies in a manner that makes you have to question their ability to read or reason, and really, you should be wondering why I'm not an even bigger asshole. You know, I really do try to be nicer when people are stupid, because it'd save me all the whining I have to listen to about how your feelings are hurt and how I'm such a horrible person. Really, though, if you were to follow the basic rule I outline below, I could be so much happier, you wouldn't whine, and I could stop trying all the time. And who knows what'd happen then, maybe we could hold hands and share secrets and have little parties where we wash each other's hair and gossip about boys, and who is dating who, and who's done what with who. It would be such a grand time, a golden age, perhaps, and our love could go down in history, like Romeo and Juliet, or Barak and Michelle, and Bill and Bush Sr (though as is typical of Bill, he's moved on to the younger man, Bush Jr. now).

Seriously, though, melatonin is quite obviously not a monoamine. It's not even an amine. It's an amide. Do sum basic lurnin and studyun. Also, take a lesson I learned early on in life: don't contradict anyone unless you're sure you know what you're talking about, and definitely don't contradict anyone in an assholish manner unless you're triple sure you know what you're talking about.

Melatonin is addictionally not metabolized by MAO, neither MAO-A or MAO-B, which, if you'd bothered to read that whole abstract (all 8 sentences, maybe), you would have realized that MAO inhibits melatonin synthesis, and with the MAOI, the synthesis inhibitor couldn't inhibit, and more melatonin was synthesized. There are numerous studies that discuss melatonin synthesis, melatonin metabolism, and they'll confirm this.
 
Smyth (a really good chemist and friend of mine)
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1. There could hardly be a worse source.
2. Since you're not british, I can only assume that your interaction with him goes no deeper than mine,
a. which makes the "really good chemist" part unverifiable, and based on lots and lots of stuff, the "really good" part should probably be removed.

Anyway, wikipedia would obviously be a better teacher.

My condition obviously has nothing to do with anything, since it seems to be more of a human trait than a bipolar one, to be an asshole when improperly contradicted.

as since I seem to get to you so badly over the measliest shit
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you mean I respond strongly when you confuse ultrabasic concepts and tell me I'm wrong? If I'm actually wrong about something, you should take the opportunity to be an ass. Just make sure that it's actually the case, because I can hardly bear your whining.
 
To save your honour rock, the other nitrogen in Melatonin (the indolic one), is actually a secondary aromatic enamine ;)
 
Cut the flame wars, guys.

If you have a correction, state it and get on with your lives.
 
I have been taking agomelatine for 3 days....

I have been getting LESS sleep :S falling asleep and sleeping ok but waking up at like 5am and not being able to go back to sleep :S

It doesnt seem to have much of an effect.... maybe I feel slightly better... music sounded quite nice this morning....

But it seems to be when you take it and the first few hours when you wake up then its pretty much wears off for the rest of the day :S

Maybe I need to give it a bit longer....
 
Unrelated, but Hammilton I loved this statement:

"My condition obviously has nothing to do with anything, since it seems to be more of a human trait than a bipolar one, to be an asshole when improperly contradicted."

I'm definitely going to steal it.
 
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