I Like to Draw Pictures of Random Molecules

[Nagelfar]

So I had this nutty idea. You can't do a front fused & a back fused tropane; the nitrogen doesn't allow the bonds, but you have things like desoxypipradrol that use two benzenes, and you have the benztropines that are sandwiched closer, why not two cycloalkane rings instead of the two benzenes, and you have the same basic structure of those desoxypipradrol-type stimulants. Since the fused tropane allows for much greater selectivity than the simple cyclohexane, why not use two *different* fused tropanes connecting to a single benzene?

Both fused rings are used from attested examples, none of my strange splicing of bonds to create weirdness, this looks weird enough all on its own:

Cleaned up:

methyl 4-{[(6R)-6-butyl-1-azatricyclo[5.4.0.0³,⁹]undecan-5-yl](phenyl)methylidene}-2-azatricyclo[4.4.1.0²,⁸]undecane-7-carboxylate

Insanity, or ingenious? (cf. these "constrained" PTs)

EDIT:

P.S., came back and re-entered it by name, and it drew it even funkier, hehe:

Anyhow those above three are all the same, here's another one based on a back-bridged & a front bridged (I believe the last one was two back bridged, I can't tell anymore, too turned around with it all):
(2Z)-2-{[(5R)-5-butyl-1-azatricyclo[4.4.0.0²,⁸]decan-4-yl](phenyl)methylidene}-11-methylidene-8-azatricyclo[5.4.0.0⁴,⁸]undecane

"Cleaned-Up":

Re-entered by IUPAC:

 

[pr0d1gy]

I've been looking into ester derivatives of tapentadol lately. Synthesis of tapentadol involves an ester intermediate so it's well documented, but I can't find anything at all about activity or lack thereof. With a propanoate ester the tapentadol seems to bear some similarity to prodine. I'm also interested in morpholine/piperidine derivatives of tapentadol though I think it's quite a stretch. The more I look into it the more I expect that dimethylamino is really the only viable substitution for tapentadol.

I'm more interested in esters of morpholines. I've searched quite a bit and haven't found much. Compounds somewhat similar to above seem to have been investigated as anticholinergic but not much else. Is is crazy to think esters or ethers such as these might have any activity as opioids?

 

[sekio]

This is cubism, not chemistry

 

[Midnight Sun]

is tert-butyl still futile?

this looked prettier in my head

 

[Dresden]

No, tert-butyl 2C is known to be active IIRC.

 

[Nagelfar]

This is cubism, not chemistry

But taken seriously, the "constrained" variants have much better selectivity for MAT, *much*, something simple piperidines don't have, for example with methylphenidate. I think this is the real golden direction to go for DARIs from what coke can tell us:

The front-bridged (on the double-bond side to the benzene) has a SERT Ki (nM) of 0.06, with NET & DAT @ >10K, and the single bond "back-bridged" one has a DAT activity of 2.23 (nM), if I connected it to the 7 instead of the 6 of the tropane, it'd similarly lower SERT affinity to well below the DAT, but much higher DAT than coke. Being able to associate to one or the other, well, who knows how that'd work. Might have a very interesting subjective effect profile. ;-p

If you don't start from the nitrogen, but from the methyl on the nitrogen's eight position (however, the method for cyclization of the compound may be trickier) you can bridge one tropane skeleton forward & backward, as like:

They also haven't bothered to go to the trouble on the back bridge to connect to both the 6 & 7 positions at once:

if you do both of the above diagrams together, the "front-to-back" bridge has as many bonds as the tropane skeleton itself. ;-p

So...

I think there's two places the benzene can be linked, the usual 3beta and a place on the front bridge, perhaps it can have both and not have the draw-backs of the benztropines

 

[crmt28]

2C-B-DragonFLY. (Not DOB-DragonFLY/Bromo-DragonFLY)

Why this one was never researched? 2C-B-FLY seems very safe. I don't see much reason for 2C-B-DragonFLY to be unsafe, since the toxicity from DOB-DragonFLY seems to be from the vasoconstriction due to the amphetamine structure.

Playing around with the molecule a bit, we can even see the trypamine ressemblance. So I came with this Dimemebfe/2C-B-DragonFLY hybrid.

Plus a closed ring version, obviously without fucking around with the alpha-position to avoid potentially deadly substances.

 

[Hammilton]

A heptacyclic (did I miss any?) cycloalkane derivative with a cyclobutyl and two cyclopropyl rings. Aside from being ridiculously bulky and unable to fit in the binding pocket, does this structure have a name?

 

[Hammilton]

I've been looking into ester derivatives of tapentadol lately. Synthesis of tapentadol involves an ester intermediate so it's well documented, but I can't find anything at all about activity or lack thereof. With a propanoate ester the tapentadol seems to bear some similarity to prodine. I'm also interested in morpholine/piperidine derivatives of tapentadol though I think it's quite a stretch. The more I look into it the more I expect that dimethylamino is really the only viable substitution for tapentadol.

I'm more interested in esters of morpholines. I've searched quite a bit and haven't found much. Compounds somewhat similar to above seem to have been investigated as anticholinergic but not much else. Is is crazy to think esters or ethers such as these might have any activity as opioids?

No, not crazy. Pretty similar to methadone type opioids of course, but yeah, also not too far removed from some anticholinergics. I'm not sure of any key structural distinctions that push the activity definitively one way or the other, but perhaps someone can chime in on that subject as I'm sure there's extant knowledge on it.

 

[Hammilton]

I think I could've shortened it by one, or maybe a double bond between the oxygens?

I don't think such a molecule could form, peroxide bonds already want to spontaneously break apart and release O2. Methoxyoxymethane does not exist so far as I can tell, and I can't imagine it forming in part of a ring, either.

 

[clubcard]

 

[clubcard]

PLEASE use this http://www.organic-chemistry.org/prog/peo/

and remember Lipinski's Rules of 5

 

[Dresden]

Without going into too much detail, I will say that the left half of this molecule is not currently hard to source at all [Hint: Open Sesame]:

3-(3,4-methylenedioxyphenoxy)tropane.

Not for this one either, obviously, but that goes without saying:

3-phenoxytropane.

 

[Dresden]

I've been looking into ester derivatives of tapentadol lately. Synthesis of tapentadol involves an ester intermediate so it's well documented, but I can't find anything at all about activity or lack thereof. With a propanoate ester the tapentadol seems to bear some similarity to prodine. I'm also interested in morpholine/piperidine derivatives of tapentadol though I think it's quite a stretch. The more I look into it the more I expect that dimethylamino is really the only viable substitution for tapentadol.

I'm more interested in esters of morpholines. I've searched quite a bit and haven't found much. Compounds somewhat similar to above seem to have been investigated as anticholinergic but not much else. Is is crazy to think esters or ethers such as these might have any activity as opioids?

It seems like to me the methyl group in the middle should be alpha to the N. But I don't claim to know.

From what I've read, though, the following is "one of the worst drug experiences ever":

2-amino-4-phenylbutane.
Likely a deliriant?

And when Sasha Shulgin accidentally made this next one (and took some), he wrote--summarized--that it, "Was an extremely weird trip that bore no resemblance to any currently known class of drugs that he had tried":

2-methylamino-4-(3,4-methylenedioxyphenyl)butane.

Since you're looking for tapentadol (Nucynta) like opiates, though, I see why the beta-carbon is methylated and not the alpha-carbon. How about this one?:

Or this?:

For IV use.

Or this, lol (no, I'm not kidding):

 

[clubcard]

As I have mentioned, you need to find the pharmocore. I think Singh's paper covers many cocaine analogues. All I know for certain is that NO ester is required for activity. If you take other DRIs like amfonelic acid & nomifensine, you should get said pharmocore. Generally, binding is based on:

-lone-pair donor (usually tertiary amine)
-aromatic having an electron-withdrawing group para to the bond through to the amine.

If you remove the aromatic amine on nomifensine, you will see that it's a semi-rigid desoxypipradrol derivative.

FORGET EXP-561. The pKa means that it passes into the brain VERY slowly. It MAY still fit the pharmocore you come up with, but trust me, the pKa leaves under 2% of the compound unionized at the pH of blood.

FREEDOM OF SPEECH

 

[Dresden]

3-(4-nitrophenyl)tropane.

Aromatic nitro compounds are generally not the safest/healthiest option for a drug. I think 4-chlorophenyl would be preferable or even 4-methoxyphenyl. In the case of the latter, would it be the paramethoxyamphetamine, which is lethal at much lower dosages than typical amphetamines, of cocaines? I think I don't want it to test on myself, anyway. And, yes, I do realize that the nitro group is about as electron withdrawing as they come.

In this forum, for example, it has generally been pretty much anathema to suggest this or its nor-methyl counterpart:

Undeserved reputation or killer death drug in the making?

 

[roi]

A (shitty) attempt at increasing phenibut potency.

 

[clubcard]

Yeeyy - the right isomer, at last. As I explained, the p-nitro was the only one as potent as C & the only one with the duration of C DUE to the nitro being reduced. Reduce it and the LogP drops through the floor and it's looking for watery, not fatty material BUT it would be a very good target for gluconation.

Other analogues (like the trifluoromethyl) were almost as potent BUT didn't give a freeze so were nasty to snort and had a LOOOOOONGGGG duration. The body can remove the N-methyl but it's still going to stay in the brain.

As I have said, the pharmocore is quite simple. The amine spatially relative to the aromatic, A tertiary amine that can donate a lone-pair, the least basic, the better so tertiary amine. That is all that is required. It's finding the same things in Nomifensine & Amfonelic acid that prove this. Often, the lipophilic pocket can fit in larger groups. I guess while looking at the 2 compounds I suggested, people would do well looking at mazindol analogues. Expanding the imidazoline to a piperazine gives x10 more dopamine affinity. Again, aromatic relative to amine.

I read in Pihkal that DON is almost as long-lasting as the halides which shows that a nitro with something ortho prevents reduction. I have a pet-theory CC DON. I think separating the isomers could produce interesting results. One isomer binds to the 5HT2a while the latter is very likely a reuptake inhibitor.

 

[Hammilton]

Have any of you bothered to compare your energy minimized structures to cocaine or other known DARI? I don't see why bothering with these ridiculously complex structures if you can't even be added to do a simple overlay.

 

[neurotic]

FORGET EXP-561. The pKa means that it passes into the brain VERY slowly. It MAY still fit the pharmocore you come up with, but trust me, the pKa leaves under 2% of the compound unionized at the pH of blood.

Why does a molecule have to be unionized to pass into the brain? I remember reading about this but I don't know why is that so

The trifluoromethyl analogue you speaked of seems like the best option of a stimulant BTW, even if it's not the most similar to cocaine. I mean no topic anesthetic properties means less messing with the heart and longer duration makes it less addicting... Cocaine's duration is what makes it a useless and too addicting drug ime