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3C-PEP - powerful & selective DA stim, v. close to opioids

Nagelfar

Nagelfar

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Nov 23, 2007
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1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine

3C-PEP_structure.png


DAT dissociation constant (Ki = 0.04 nM)
NET (Ki = 1107 nM )
SERT (Ki = 802 nm)

"10,000 times more potent than cocaine as a dopamine transporter inhibitor in vitro"

...and look how close it is to some of the fastest onset, short duration, opioid analgesics(!)

Fentanyl:

220px-Fentanyl2DCSD.svg.png



MT-45:

180px-MT-45_svg.svg.png
 
Interesting, anyone know what the dissociation constants are for fentanyl and open chain derivatives itself?
 
aced126 said:
Interesting, anyone know what the dissociation constants are for fentanyl and open chain derivatives itself?
Click to expand...

For MAT/DAT? If they were of note I'm sure that'd be pointed to in the literature somewhere in more than a passing manner, I'm sure they're very high numbers (non-efficacious as a MAT ligand)

My interest is that the opioid agonism of the G-coupled receptors and the MAT ligands are tersed so closely, but rarely seem to overlap. I can only think of pethidine and lefetamine; but the later is only near to codeine and there are so many that appear on the fentanyl spectrum of strength.

I think the ideal compound (for my own twisted motives) would be a stimulant of slightly longer duration and roughly approximate strength / selectivity to cocaine, that when metabolizing in-vivo becomes a morphine-comparable opioid (completely masking the subjective "stimulant-crash" of the initial onset MAT ligand effect. ;-p )

...with all the exponential >trillions of drug-like neuroactive molecular conformations possible, a hand-full have *gotta* exist. :p
 
It's an antidepressant prodrug. Lose the N-PEA and you get m-chlorophenyl piperazine.
 
Weird stuff, but MT-45 isn't exactly that potent as an opioid if I'm right?

Let's hope they won't sell it anytime soon as RC Krack, 1:100 inositol mixture ... I tend to think that pure DAT inhibitors aren't overly toxic in the end, but anything so potent shouldn't be made available for sure.
 
clubcard said:
It's an antidepressant prodrug. Lose the N-PEA and you get m-chlorophenyl piperazine.
Click to expand...

When you said "anti-depressant" I surfed through a couple of WP internal links and found NRX-1074 which is a "selective partial agonist of the glycine site of the NMDA receptor which is under investigation as a novel antidepressant drug", which sounds interesting for completely other reasons
 
A selective DRI? looks neat.

Although at first glance that must alo have horrible horrble PK problems... I bet it aggregates as well as has awful solubility in water.
 
sekio said:
A selective DRI? looks neat.

Although at first glance that must alo have horrible horrble PK problems... I bet it aggregates as well as has awful solubility in water.
Click to expand...

What? The first one in OP? What makes you think that?
 
sekio said:
A selective DRI? looks neat.

Although at first glance that must alo have horrible horrble PK problems... I bet it aggregates as well as has awful solubility in water.
Click to expand...

What is aggregation? Would the salt of this not have water solubility problems?
 
Takes even less time to revert such changes and let you try again.

If you can't follow the few simple steps listed on there..just don't.
 
aced126 said:
What is aggregation? Would the salt of this not have water solubility problems?
Click to expand...

It should have no solubility problems in water as a salt, and it'd be protonated at physiological pH. Unless sekio is aware of something about that molecule that I'm not.

Aggregation is related to colloids, as in it would form clusters forming a suspension. But that only happens with things that don't form a homogenous solution on the molecular level in a given solvent, aka aren't soluble in the solvent.
 
Hey, got some tables, proves opioid affinity to some degree. ;-j

LXkpGo.jpg

pIOYMu.jpg
 
@nag: I am not sure if Ki of 4600nM qualify as active! .. but since you like tropanes so much, here is one with OP activityt
180px-Azaprocin.png

About 10x morphine..The 4-nitrophenyl is about 25x more than morphine (mu agonist) or ~1/3-1/4 fenta. the open chain piperazine with the N4 propionyl replaced by a butyryl is about same as morphine (used clinically in China to treat serious pain like cancer pain!)...

wp entry Azaprocin
Azaprocin is a drug which is an opioid analgesic with approximately ten times the potency of morphine, and a fast onset and short duration of action.[1][2][3] It was discovered in 1963, but has never been marketed. The derivative substituted on the phenyl ring with a p-nitro group is more potent than the parent compound, around 25x the potency of morphine.[4] The ring-opened 2,6-dimethylpiperazine analogues are also active,[5] and a large family of opioid analgesic compounds derived from this parent structure have been developed over the last 40 years.[6][7][8][9][10][11][12][13][14][15] One analogue, AP-237, is widely used in China to treat the pain caused by cancer.
Click to expand...

@nag: would replacing the propanoyl with a methyl give cocaine-like DATs???? I mean N-CO-Et-----> N-Me or even the potential metabolite of azaprocin (N-CO-Et ---> NH) Could be a DAT inhibitor?
 
Perhaps. The nitrogen doesn't at first seem like its in the right place but for the length of that methyl-styrene(?) it very well could be. It's the acyl at the other nitrogen that is messing it up, if comparing to cocaine N8 modified ligands. But whose to know.
 
or even this?
can4vas_zpsuf2ed9lr.png


what do you think? since you very well read on SAR of tropanes and related DRIs? may be a naphthylmethyl instead of the cinnamyl? I mean:

canvas44_zpshewmitgz.png
 
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