I Like to Draw Pictures of Random Molecules

[Nagelfar]

what do you call that last tropane?..

methyl (5S,6S,9S)-9-methyl-2-[(1R,2R,5S)-8-methyl-1'-(1λ⁶-thiopyran-1-ylidyne)-8-azaspiro[bicyclo[3.2.1]octane-3,3'-[1λ⁶,4]thiazole]-2-yl]-1,4-dioxaspiro[4.5]dec-2-ene-6-carboxylate

does it smell???

It isn't complex enough of a structure to constitute an olfactory organ. So it doesn't have the ability to smell you, worry not, your remaining stash won't shy away from you when you've been in your attic sweating for three days in a row awake on it.

 

[aced126]

Dotchem, if 2-napthylisopropylamine binds similarly to MDMA, that suggests the napthyl moiety is bioisosteric with the 1,3-benzodioxol-5-yl moiety. We know that the latter moiety is bioisosteric to benzofuran, which is bioisosteric to indole.

 

[roi]

The N-methyl analogue of that (Methamnetamine) is being sold on the grey market and rather similar to MDAI - too sedating on its own, needs to be combined with a stimulant.

EC50 values:

Naphthylaminopropane: 3.4 nM SERT, 11.1 nM NET, 12.6 nM DAT

Methamnetamine: 13 nM SERT, 34 nM NET, 10 nM DAT

Surprisingly the SERT:NET ratio stays about the same and only DAT is weaker.

Also at least the N-methyl is about as potent as MDMA.

 

[atara]

Dotchem, if 2-napthylisopropylamine binds similarly to MDMA, that suggests the napthyl moiety is bioisosteric with the 1,3-benzodioxol-5-yl moiety. We know that the latter moiety is bioisosteric to benzofuran, which is bioisosteric to indole.

Bioisosteres aren't transitive. If you have an 80% match with an 80% match with an 80% match, you end up at just 51%.

But IIRC benzofuranyl is closer to naphthyl than either is to benzodioxolyl. There's not a whole lot in the way of bioisosteres for simple aromatic ethers except the toxic-looking 2,1,3-benzothiadiazole.

 

[DotChem]

Dotchem, if 2-napthylisopropylamine binds similarly to MDMA, that suggests the napthyl moiety is bioisosteric with the 1,3-benzodioxol-5-yl moiety. We know that the latter moiety is bioisosteric to benzofuran, which is bioisosteric to indole.

aced126: that's right: the naphthyl in that case is a good bioisosteric replacement of the benzodioxolyl at least as far as binding to DAT SERT NET in ratios similar to MDMA is concerned.

but it is a bit more complicated since we're dealing with multiple targets here.

Ex: naphyrone

IC50 SERT 46.0nM
DAT 40.0nM and
NET 11.7nM


But MDPV"

IC50 SERT 3370nM
DAT 105.4nM
NET 95.0nM

In this case, benzodioxolyl -> naphthyl replacement doesn't work as intended. One is stim (MDPV) the other empathogen. So I think the concept doesnt work everytime especially with drugs targeting multiple receptors/transporters at the same time..etc .

 

[DotChem]

Bioisosteres aren't transitive. If you have an 80% match with an 80% match with an 80% match, you end up at just 51%.

But IIRC benzofuranyl is closer to naphthyl than either is to benzodioxolyl. There's not a whole lot in the way of bioisosteres for simple aromatic ethers except the toxic-looking 2,1,3-benzothiadiazole.

how about?

the benzoxazole has pretty much similar steric, hydrophobic and electronic properties to the benzodioxole. The thiazole is a little more hydrophobic but i don't see why it shouldn't work. Have those being tried?

MDMA logP = 1.86 PSA = 30.49
BzXMA logP = 1.59 PSA = 38.06
ThZMA LogP = 2.38 PSA = 24.92

 

[aced126]

Thiazole derivative should in theory be the most effective

 

[roi]

Stimulating dissociative psychedelic

#believe

 

[pharmakos]

lol :D

did the guys that did the research on NBOMes ever play around with substituting piperidine derivatives on the nitrogen? if so, i think we can make that molecule even more ridiculous.

 

[Midnight Sun]

lol :D

did the guys that did the research on NBOMes ever play around with substituting piperidine derivatives on the nitrogen? if so, i think we can make that molecule even more ridiculous.

I think something like this would be better https://en.wikipedia.org/wiki/25I-NBMD

cuz it adds another methylenedioxy

 

[pharmakos]

 

[Incunabula]

norketobemidone is responsible for the NMDA-antagonist properties of ketobemidone. I wonder how strong, and recreational, it is as a NMDA-antagonist? And I wonder if it is an interesting avenue to explore for new RC dissociatives?

 

[Dresden]

LEVORPHANOL, a potent morphinan opiate.

LEVORPHANDIOXOLE

ISOLEVORPHANDIOXOLE

TRIMETHOXYLEVORPHANOL

LEVORPHANUTMEG

ISOLEVORPHANUTMEG

APIOLEVORPHANOL

CHLOROLEVORPHANOL

This is a pretty clever series, one that combines some of the essential spices with a simple, easy to synthesize morphinan based opiate to hopefully yield some new psychedelic or entactogenic opioids.

In unrelated news:

and

These last two simply scream, "MAKE ME!"

 

[DotChem]

3C-PEP

1-(3-Chlorophenyl)-4-(2-phenylethyl)piperazine
Pure DRI with no significant SERT NET or Opioid activity..about 10,000 times more potent than cocaine as Dopamine Reuptake Inhibitor (IC50 = 0.04nM v IC50 = 461nM at DAT)
But logP = 4.55 PSA = 6.49 too lipoliphilic (fat depot).. slow onset of action ..now + a methylenedioxy and pyridine bioisostere replace phenyl ( I love pyridines!

IED
at least as potent as 3C-PEP (ie 5-10,000x cocaine) I bet!...but with
LogP = 2.35
PSA = 37.83

compare to cocaine
LogP = 2.28 PSA = 55.84


now fast and furoius acting .. IED (Improvised ExplOsive Drug)

 

[Nagelfar]

STOP THE PRESSES!!!

I had an epiphany leaving the library.

The hydrogen bond acceptor @ MAT is what gives the C2 substituent greater affinity, but the steric bulk of a big substituent at that two position can cause the tropane ring to flatten and distort, ruining the binding efficacy of the rest of the molecule. The acceptor only increases if its in the beta/rectus configuration. But since benzoyltropane has more affinity than benzoylecgonine (just not benzoylmethylecgonine; and remember it is de-methylated in vivo)

Why not this?:

So simple, yet never done. Is it unstable or something? Just make the basic hydrogen non-planar (in a beta-configuration). I may be on to something here...

 

[roi]

Can you draw anything else than phenyltropanes btw? I mean...what's the point?

 

[sekio]

Nag, you just drew tropacocaine? I think it's known but a shitty stimulant...

 

[pharmakos]

looks like the sort of thing that would need a stereoselective synthesis to be effective. there are quite a few possible isomers there.

 

[aced126]

Which hydrogen is the basic hydrogen?

 

[Dresden]

I like to trip hard.