RCs 3F-Phenmetrazine (3-FPM)

[Jekyl Anhydride]

Doesn't a lower value usually mean that a drug is *stronger*?

Yeah, I think those numbers aren't "release", they're either IC50s for reuptake (in nM) or transporter Ki (in nM). In all cases, the smaller the more potent.
.

Sorry, should have stated that more clearly.
-~-

Below is a table showing 3-FPM's potency for inducing release (EC50) of dopamine (DA), serotonin (5-HT) and noradrenaline (NE) in comparison to phenmetrazine:

*Compounds- Neurotransmitters V	3-FPM/ PAL-593	Phenmetrazine
DA Release	43	87
5-HT Release	2558	3246
NE Release	30	38

*Phenylmorpholines and analogues thereof

*C07D265/30 1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

https://patents.google.com/patent/US20130203752

 

[gymstud]

Anyone tried both??

 

[gymstud]

The numbers only tell us so much

 

[Scrofula]

They tell us it's more potent than cocaine . . .

 

[Coolwhip]

Which doesn't mean anything. Cocaine isn't known to be very potent in the first place, but that doesn't stop it from being extremely euphoric, fentanyl analogs are hundreds of times more potent than morphine, but morphine is soooo much better. Assuming acquiring a recreational amount isn't so hard as to deter use, then potency has less than jack or shit to do with a drugs potential for abuse or euphoric effects.

 

[Scrofula]

The question was what the numbers say, it wasn't an endorsement. Big message the numbers give: Lack of SERT inhibition. I think that uniquely coke trait is why cocaine is so much more sociable than meth. And a lot of cathinones, apparently.

 

[crOOk]

The question was what the numbers say, it wasn't an endorsement. Big message the numbers give: Lack of SERT inhibition. I think that uniquely coke trait is why cocaine is so much more sociable than meth. And a lot of cathinones, apparently.

Are you basing your statement on receptor affinities? That is not necessarily the conclusion one should draw. Jusst look at DMT's s1r affinity. It doesn't explain the strong activation of said receptor at all (VMAT2 releases it close to the receptor sites on the ER).

The affinity also says nothing about the exact way the receptor reacts to the transmitter/drug.

Plus, a drug doesn't need affinity to SERT, there are many other ways for it to act serotonergic. Downstream activation or binding to other proteins that raise serotonin activity.

I don't know whether or not methamphetamine is serotonerguic at all though, I don't mean to contradict you with what I said.

"The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974310/

https://www.ncbi.nlm.nih.gov/pubmed/10987842

Regarding 3-Fluoro-Phenmetrazine... I am convinced it has significant serotonergic effects which becomes very apparent at high doses. My eyelids will just drop after an IV injection of more than 500mg. :D

EDIT: Speaking of s1r activation, it seems it strongly contributes to the desirable effects in both cocaine and methamphetamine, as well as many drugs from other classes.

 

[Scrofula]

Based on IC50 for reuptake, among other things.

That would be a direct measure of the receptor's function, no need for vmats or affinities or invoking the dreaded endoplasmic reticulum.

Speaking of non-cocaine stims in general anyway, which are a long way from tryptamines.

But I'll spare you the trouble and point out that these are radiolabeled in vitro assays. I'm sure a magical new property is produced by one's vital essence interacting with the drug, making it wonderfully euphoric and sociable.

Why would your eyelids "dropping" be an indicator of serotonin release and/or reuptake inhibition?

 

[crOOk]

But I'll spare you the trouble and point out that these are radiolabeled in vitro assays.

I'll just take your word on that, since I have not looked into it myself.

I'm sure a magical new property is produced by one's vital essence interacting with the drug, making it wonderfully euphoric and sociable.

Exactly. It doesn't really matter whether or not a drug binds to a certain protein. That's why I mentioned downstream mechanisms. These do not necessarily noticeably need more time to manifest. As stated in the article I quoted SERT seems to be inhibited very rapidly upon injection of methamphetamine.

Why would your eyelids "dropping" be an indicator of serotonin release and/or reuptake inhibition?

For what it's worth that's just my experience. Not trying to convince you of anything! There is no doubt in my mind that you, too, have ways to tell what drug you are or another person is on.

I could most definitely tell when I've been given a glutamatergic dissociatives, opiates, GABAergic drugs etc.
The conclusions I draw from the subjective effects a drug gives me can always be wrong, but they rarely are. This may mean nothing to you, but before a drug is thoroughly researched I need ways to guess what may be happening in my body.
When you see a patient with slowed shallow breathing and constricted pupils you will probably assume he has used opiates, even if you can't find any opiates in his blood. At the very least you would assume he used a CNS depressant. These things can be observed and measured, by both the subject itself as well as other people.
My eye lids drop in very distinct way while my pupils dilate (we've all seen people rolling balls) which is accompanied by a number of other effects I associate solely with serotonergic drugs. This doesn't mean that all serotonergic drugs will produce said symptoms, e.g. psychedelics don't, cocaine doesn't either.

And the discrepancy between the mentioned lack of SERT inhibition in the findings you referred to on one hand and the observed in vivo SERT inhibition in the articles I linked on the other is why I often trust my body and experience more than I trust early binding essays of novel drugs. Most researchers would not assign any value whatsoever to my impressions, might even look down on my approach.

I may be wrong. But I am personally pretty positive 3FPM is serotonergic once the dose is upped far enough. In lower doses I noticed no effects hinting at serotonergic activity. It felt more like a serotonin releaser at those very high (IV!) doses.

 

[Scrofula]

No, that's great you're in touch with your personal biological quirks involving your drug use. Sounds like how I know the coke is good, when I have to take a big shit with the first line. And then tell everyone at the party about it.

I'll just take your word on that, since I have not looked into it myself.

The OD forum motto, especially after looking into something.

Exactly. It doesn't really matter whether or not a drug binds to a certain protein.

I was making fun of you with the vital essence. Of course it matters how tightly a drug binds to a certain target. A lot of people walking around today do so because naloxone binds tighter than almost all other opioids. The opioid that doesn't bind to the MOR at all, yet triggers the same effects and still provides a rush worthy of becoming an IV drug of abuse, I'd like to see.

Is affinity the only story? Of course not, or my sertraline would be a lot more popular, considering it binds to DAT tighter than methylphenidate. But you're not going to get strong serotonergic effects without affinity for one of the receptors involved, either. And there is serotonergic reuptake data, at least, for a lot of cathinones, and I'm sure a lot of phenylmorpholines too.

While keeping in mind that SSRIs do inhibit reuptake, and yet aren't exactly club drugs.

Not that I made a single claim about the drug in the title as relates to serotonin. I used meth and cocaine as examples. Someone kept pressing on a throwaway line, though.

 

[crOOk]

No, that's great you're in touch with your personal biological quirks involving your drug use. Sounds like how I know the coke is good, when I have to take a big shit with the first line. And then tell everyone at the party about it.

LOL! A foaf used to get the shits as soon as he'd know the dealer was on his way over. Like the dog that begins salivating once it hears the bell ring. :D

I was making fun of you with the vital essence. Of course it matters how tightly a drug binds to a certain target.

Of course it matters. But the fact that a certain drug does NOT bind to a specific target - the serotonin transporter - doesn't allow us to conclude that the drug will not act serrotonergic.

Affinity will obviously tell you how much of a drug will be bound to a target and how much of it will not. Given the affinity and activity of his substance around the receptor and the activities and affinities of other competing ligands leaves us with a simple mathematical problem. I know you know this very well, just making sure we are on the same page.

A lot of people walking around today do so because naloxone binds tighter than almost all other opioids. The opioid that doesn't bind to the MOR at all, yet triggers the same effects and still provides a rush worthy of becoming an IV drug of abuse, I'd like to see.

Me, too. :D
However we weren't talking about opioids, but about methamphetamine. It apparently inhibits SERT very rapidly without directly binding to it. Possible reasons could be downstream processes (after the substance triggers of a signal cascade) or a metabolite doing the job, but there are probably other scenarios I am not thinking of.

Not that I made a single claim about the drug in the title as relates to serotonin. I used meth and cocaine as examples.

Yeah I know. I was referring to meth in particular here.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2000.0751608.x

 

[Scrofula]

We were talking about 3F-phenmetrazine.

And I was talking about subjective aspects of a high.

I mean, acetylcholine will be involved in all these drugs too, because you need to move your arm to get them.

ETA: tbc, that's aspects of a "high". Every psychoactive drug is going to involve every transmitter eventually. Usually you need a more immediate interaction to get an experience worthy of placing it on a controlled substance list.

 

[crOOk]

We were talking about 3F-phenmetrazine.

And I was talking about subjective aspects of a high.

I mean, acetylcholine will be involved in all these drugs too, because you need to move your arm to get them.

ETA: tbc, that's aspects of a "high". Every psychoactive drug is going to involve every transmitter eventually. Usually you need a more immediate interaction to get an experience worthy of placing it on a controlled substance list.

Nope. The sole reason I replied was because you talked about serotonergic effects of coke which meth is lacking. I might not have made the clear enough, but check my first reply to your post.

Alas it seems we aren't getting anywhere in this dialogue. I never meant to argue with you and I still don't.
I was hoping to gain some insights. I don't.

This is not a discussion which we both could've come out of more knowledgeable than before.

However, since it apparently turned into an argument in which striving for truth doesn't count for shit but being right does, I need to get this off my chest:

Lack of SERT inhibition. I think that uniquely coke trait is why cocaine is so much more sociable than meth. And a lot of cathinones, apparently.

You, sir, are wrong! ;p

You also can't handle this situation at all it seems. Your ACH comment was plain erratic.

 

[Scrofula]

Good morning to you too. I'd say, I have the numbers to back me up on the SERT thing, like how non-fluorinated phenmetrazine has an EC50 of 7uM for serotonin release, but then you'd conveniently say, "but the numbers don't mean anything. Release isn't even about SERT. ANd my eyelid drooped!"

And you'd be right, how can I possibly refute evidence like that. Clearly my random statement had no place in this thread.

 

[gymstud]

I don't know about any numbers UT it's best drug I've ever taken

 

[crOOk]

Good morning to you too. I'd say, I have the numbers to back me up on the SERT thing, like how non-fluorinated phenmetrazine has an EC50 of 7uM for serotonin release, but then you'd conveniently say, "but the numbers don't mean anything. Release isn't even about SERT. ANd my eyelid drooped!"

And you'd be right, how can I possibly refute evidence like that. Clearly my random statement had no place in this thread.

You twist my words. In vitro essays like that are no absolute proof there is no SERT inhibition in vivo.

SERT inhibition can happen indirectly, 'downstream'. There is SERT inhibition as has been demonstrated many times, even if methamphetamine itself does not bind to the receptor itself.

In vitro binding essays are performed to give us an idea of what could be happening in vivo, they don't allow us to deduct what 'can not' happen in vivo.

So, you are right that Meth isn't an antagonist of SERT. However taking it rapidly inhibits SERT to a clinically significant degree. This does not happen to ACH or androgen receptors lol.

I honestly don't know how we could be arguing against that. Neither do I know what there is to gain by not listening to each other, let alone twist each others' words as you have been doing relentlessly since this conversation began.

I would love to gain some insights from you, but we are really not getting anywhere like this. :/

 

[Scrofula]

Think its safe to say 3f-Phenmetrazine is not a serotonin releasing agent, or, you haven't taken any in quite a while. Either way, I'm not to keen to try it anymore. Has this shown up in Florida yet?

 

[Coolwhip]

SERT isn't a receptor, and cannot be inhibited indirectly...

And as far as recreational drug effects go, there is a huge, huge difference between something increasing the release/firing of 5-HT downstream because of its actions on DA/NE; and being a SERT inhibitor or releasing agent. IME there is nothing that stands out as serotonergic about the 3-FPM experience, although I agree it is less paranoia/anxiety inducing than many stims, I would attribute this more to its almost equal action at DA and NE as opposed to most stims having about double the EC50 for NE and also which areas of the brain is targets the most.

 

[crOOk]

Think its safe to say 3f-Phenmetrazine is not a serotonin releasing agent, or, you haven't taken any in quite a while. Either way, I'm not to keen to try it anymore. Has this shown up in Florida yet?

Oh I wasn't aware it is safe to say that. In that case you are obviously correct. I am aware that the subjective impression I got from 100s of injections north of 500mg (below which I don't recognize serotonergic effects) counts for very little.

Nonetheless, you're gonna have to understand that your statement counts for just as little, considering you just stated methamphetamine wasn't serotonergic.

That leaves us both where we started. Such a productive conversation.

 

[Scrofula]

No, I'm way back up there with "more potent than cocaine" still. I thnk phenylmorpholines must have toxic effects on central cholinergic circuits. Maybe peripheral too, since it only takes a middle finger to scroll up the page and read. Definitely not a thread endorsing the stuff.

And still more productive than the latest scoop on the Immodium crackdown, I will say that.