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I Like to Draw Pictures of Random Molecules

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Friman1987 said:
What do you think about these molecules?
gxNp8EP.jpg
Click to expand...

Should work in principles as agonist or at least partial agonists. Similar molecule

canvas4_zpspjyntyir.png
Ki at mu = 0.021 uM(agonist) (compare to morphine Ki = 0.0026uM). So I guess adding phenethyl should get at least 10X (note this molecule is kind of not good example!) yours should be more close relative of morphine. Anyway yeah we got carried away threading opioids from the psychedelic LSD naphthalenes (benzo indole) congeners discussed earlier:)

Now, the pyrrolidino tetrahydro naphthalene you suggested, look like a cyclized version of prolintane (might well be stim+opioid ie speed ball !)

220px-Prolintane.svg.png
 
I don't know about all those designer tetralin opioids, but I know that

2-aminotetralin.png


2-AMINOTETRALIN

is bad news (like hospital news) at or above 100mg, which admittedly doesn't say anything much about yours necessarily.
 
using this image of DOI docked in 5HT2a (from http://www.bluelight.org/vb/threads/591265-modeling-the-5-HT-2a-receptor

doi.png


there's a perfectly good spot to improve binding @ serine 159 but as you can see the nitrogen is already in its optimal position courtesy the alpha carbon - precluding any vanilla phenmetrazine derivatives for a multitude of reasons

with that in mind, anyone think this would work?

fEwZrGG.png
 
Switch oxygen and amine, remove the N-methyl group and it'll work ;)

There's a paper on 2C-B-Norphenmetrazine somewhere out there. Kinda annoying synthesis, like 5 steps from bk-2C-B iirc...
 
roi said:
There's a paper on 2C-B-Norphenmetrazine somewhere out there. Kinda annoying synthesis, like 5 steps from bk-2C-B iirc...
Click to expand...

I was trying to avoid this; one of the aforementioned reasons I cited phenmetrazine psychedelics as being a no-go is because constraining the nitrogen neuters its binding ability. I would believe it still can, but it won't do it very well. Then there's the matter of how it sits in 3D space...

I oriented the oxygen intentionally to get it as physically close to the residue as possible while still (hopefully) permitting the nitrogen to bind unhindered and still in the same "optimized" position that alpha-methylation provides. Unconventional indeed

Another pose:
UlwzdOK.png

(I think I drew that right but I'm also quite hungover)
 
I'd like to see someone try going though a few permutations to find a potential cannibinoid-antagonist opioid-*agonist* (unlike the several cannibinoid + opioid-antagonist/inverse-agonist that seem to come hand in hand)
 
It's not really a good leaving group, is it? pKa is 14.5, so it's only really a slightly better leaving group than alcohols (which aren't great leaving groups). You've also got the amide nitrogen lone pair (as well as being delocalised into the imidazole ring) contributing to N-C pi bond character, which makes that carbon less electrophilic to nucleophiles. So I wouldn't really say it's irreversible, but correct me if I'm wrong.
 
Actually simple imidazole pKa = 6.99 at 25 °C (CRC Handbook of Chemistry & Physics) so it is way better leaving group than RO-. Not as good as Halo or even acetate (pka 3-5) but under the right conditions (eg with relatively strong nucleophiles) carbonyl imidazoles will react. Thats' why for example carbonyl-diimidazole (Im2C=O) is used as safer replacement of phosphege (Cl2C=O) to acylate amines or activated carboxylic acids. But yeah you're right the presence of the other nitrogen will certainly make this molecule even less reactive. But my take is that primary amines in protein (eg lysines - relatively strong nucleophile) may react and give irreversibly acylated protein. Under the right conditions! But who knows? hard to explain why this guy has his brain fried by this molecule!
 
Dresden said:
is bad news (like hospital news) at or above 100mg, which admittedly doesn't say anything much about yours necessarily.
Click to expand...

you sure? why so? i was kinda interested in aminotetralin and its possible derivatives a while ago but wasn't able to find almost any info on it and the N-methyl homologue at all.
 
DotChem said:
Actually simple imidazole pKa = 6.99 at 25 °C (CRC Handbook of Chemistry & Physics) so it is way better leaving group than RO-. Not as good as Halo or even acetate (pka 3-5) but under the right conditions (eg with relatively strong nucleophiles) carbonyl imidazoles will react. Thats' why for example carbonyl-diimidazole (Im2C=O) is used as safer replacement of phosphege (Cl2C=O) to acylate amines or activated carboxylic acids. But yeah you're right the presence of the other nitrogen will certainly make this molecule even less reactive. But my take is that primary amines in protein (eg lysines - relatively strong nucleophile) may react and give irreversibly acylated protein. Under the right conditions! But who knows? hard to explain why this guy has his brain fried by this molecule!
Click to expand...

The pKa you describe is the one for imidazole which is already protonated, that is to say: imidazole(H+) <---> imidazole + H+; pKa=6.99
However, imidazole <-----> imidazole- + H+; pKa = 14.5. The only reason why the pKa of this acid-base reaction is way less than it should be (see ammonia pKa = 32.5) is because when deprotonated, the lone pair can delocalise into the imidazole ring and Huckel's rule is satisfied (the system gains extra stability from aromaticity).

Also lysines aren't really good nuclephiles because they're pretty much always charged, so the nitrogen lone pair is mostly unavailable. In hydrolytic enzymes, lysine is almost always never used as the nucleophile in the active site. It is normally serine or cysteine (which is first deprotonated by a base like histidine so nucleophilicity of the serine or cysteine residue is increased).
 
aced126 said:
The pKa you describe is the one for imidazole which is already protonated, that is to say: imidazole(H+) <---> imidazole + H+; pKa=6.99
However, imidazole <-----> imidazole- + H+; pKa = 14.5. The only reason why the pKa of this acid-base reaction is way less than it should be (see ammonia pKa = 32.5) is because when deprotonated, the lone pair can delocalise into the imidazole ring and Huckel's rule is satisfied (the system gains extra stability from aromaticity).
Click to expand...
You are absolutely right on the pKa values because imidazoles are amphoteric (base and acid) so naturally you'll have 2 pKas. But the pKa that matter for the reaction I was mentionning is that of the the acid: ImH+ <------> ImH . The reason being at physiological pH (7.4) major form is ImH+ (not that much but at least 20%more than the neutral form). Like this in the case of acyl-imidazoles like in the cannabinoid molecule :

canv3as_zpsexoox4p1.png




So the pKa to use to measure the leaving group abilitity of imidazole in that case should be the acid one (6.99). as the leaving group is ImH (not Im(-).. Does that make sense?
You can see from example above(oversimplified of course! not taking account substitution or other factors).

aced126 said:
Also lysines aren't really good nuclephiles because they're pretty much always charged, so the nitrogen lone pair is mostly unavailable. In hydrolytic enzymes, lysine is almost always never used as the nucleophile in the active site. It is normally serine or cysteine (which is first deprotonated by a base like histidine so nucleophilicity of the serine or cysteine residue is increased).
Click to expand...
True Lysines are poor nucleophiles at physiological pH(7.4) but not always. Some lysines in proteins are actually quite good nucleophile by happening to be either in a basic microenvironment where pH is relatively basic (eg in some cell organelles eg lysosomes pH can be as high as 10!!!). Or made "basic" for example by nearby groups eg the Imidiazole =N of histidines. it all depends on the protein structure microenvironment in which the lysine located. BUT you are absolutely right at physiological pH (7.4) most lysines will be protonated therefore not nucleophilic.
As for the cannabinoid molecule, that got this guy brain dead, who knows? would be interesting to know how the molecule act endocannabinoid reputake inhibitors en general


(may the man who's got his brain fried RIP.. he passed away.. 5 remained in hospital brain dead.
 
Oh yes my bad, the imidazole wouldn't be a bad leaving group I guess, at physiological pH. Still not as good as acetate or chlorine or anything.
 
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The aminoindanes have been shown to cause less neurotoxicity. One explanation is the prevention of the alpha-methyl carbon easily forming radicals.

2-(pyrrolidinyl)-indane.png

1-methyl-2-(pyrrolidinyl)-indane.png

1-oxo-3-methyl-2-(pyrrolidinyl)-indane.png

5%2C6-methylenedioxy-1-oxo-3-methyl-2-(pyrrolidinyl)-indane.png

5%2C6-methylenedioxy-1-oxo-3-ethyl-2-(pyrrolidinyl)-indane.png
 
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