I Like to Draw Pictures of Random Molecules

[Nagelfar]

I wonder if structures like this:

bicyclo[2.2.2]octa-1,3,5,7-tetraene

this:

tricyclo[4.4.0.0³,⁸]deca-1,3(8),4,6,9-pentaene

or this:

tetracyclo[6.4.0.0⁴,⁹.0⁵,¹²]dodeca-1(12),2,4,6,8,10-hexaene

can exist in nature? essentially a benzene ring (instead of a cyclohexane ring) with an endo-etheno-bridge type structure in the center.(?)

 

[sekio]

No, they violate Bredt's rule.

Also, looking at your structures again..

I can count 3 violations of conventional organic chemistry knowledge in that little bit. A hemiaminal is normally not stable (loses water to an imine or hydrolyses to a ketone), a hemiaminal hydroxylamine even less so, and there's even a Bredt's rule violation

The only other drugs that have carbomethoxy groups on them are stuff like cocaine and the phenyldates

 

[Nagelfar]

Also, looking at your structures again..

I can count 3 violations of conventional organic chemistry...

Perhaps it's a 2-quinuclidonium tetrafluoroborate like anti-Bredt molecule ;-P

You mean by that image not my benzene bridges but my morphine hybrid as well? I left an oxygen off because it would violate physics but my molecular building engine didn't catch any other exception, though I would almost guarantee it not be fool-proof.

 

[sekio]

Both those molecules you drew have that same moiety in them.

 

[Nagelfar]

Both those molecules you drew have that same moiety in them.

Yeah the tropane/ecgonine (which is what I added to the ring in the morphine backbone while keeping some of its nuances like the double bond therein) is already quite bulky. Both are hard from-scratch synths as I understand it. So I'm not taken-aback when I find combining them to be a feat of impossibility. ;-p

What, so is this similarly alien to real-world physics? (My cocaine-ibogaine hybrid):

 

[atara]

literally mdma tho

 

[Nagelfar]

phenyl-methylphenidate alterations

It's interesting to note if you look at cocaine from an other-than-usual perspective:

It appears much like this analog of methylphenidate which has a phenyl for the benzene:

...and yet this "phenyl"-methylphenidate's binding potency is >5000 (bad affinity) whereas regular MPH is 324

I wonder if you changed the acetyl/acetate to the nitrogen like on cocaine if it'd be better, or is it the nitrogen that needs to be moved further away on the piperidine ring like the nitrogen is on the tropane of cocaine, or is the lack of oxygens on the phenyl a problem (from the example of phenyltropanes I wouldn't think this to be a necessity)? Does anybody have any DRI examples that would lead one more to changing the nitrogen or the acetyl as a higher priority for giving this 'phenyl' methylphenidate derivative more potency?

The 2-naphthyl MPH analog (i.e. HDMP-28) does such a thing (e.g. DMNPC), but it displays affinity either way:

So I'm leaning to changing just the nitrogen; making: "methyl 3-phenyl-2-(piperidin-4-yl)propanoate"

Any thoughts?

 

[adder]

DMNPC is like a naphthyl analogue of phenyltropane without the additional dimethylene bridge on the piperidine.

Also, drawing molecules like these on paper without keeping proper conformation of piperidine or tropane rings is pointless as you're going to draw false conclusions.

CPT, DMNPC, d-threo-methylphenidate

Methylphenidate likely interacts with DAT in a different manner from cocaine and phenyltropanes.

 

[Nagelfar]

Methylphenidate likely interacts with DAT in a different manner from cocaine and phenyltropanes.

In fact they're closer than many other MAT inhibitors, this 2014 publishing (pdf file) elucidates that their (cocaine & methylphenidate both) binding site is distinct from that of other reuptake inhibitors, being at TMs 9-11 on DAT whereas others bind to TMs 10-12 (with overlapping loci for them and others at 1 & 7 additionally). (They are also tentatively classed, according to that paper, together as 'inverse agonists' in a form of positive allosteric modulation of DAT which other SNDRIs do not do)

Also, is there really a methyl on the nitrogen of the piperidine of d-threo-methylphenidate?

Anyhow to further illustrate the similarity of the phenyl/benzoyloxy-tropanes and the methylphenidate class of DRIs with respect to their binding compare the below:

It's β-CFT (a.k.a. WIN 35428, a.k.a. 4'-fluoro-troparil) overlayed with HDMP-28 (a.k.a. methylnaphthidate), which is not even using the DMNPC orientation of the methyl-acetate-like (which is at the 2β position in the enumeration of the cycloheptane ring numbering of cocaine & cocaine-like/phenyltropane structures) functional group, but the purely MPH placement.

 

[adder]

Yeah, there's no methyl on the methylphenidate's amine, I simply copied and pasted N-methylpiperidine, and then forgot to delete the methyl group.

Now that I compare them, the placement of the amine and the ester is almost exactly the same with a two-carbon spacer. Only the aromatic ring in phenyltropanes is farther from the amine, so that also explains why methylnaphthidate has a higher affinity than methylphenidate itself does. I guess I had a bad day yesterday.

 

[roi]

Methylenedioxypyroamphetamine, because why the fuck not?

 

[neurotic]

Is the molecular structure of DAT known or anything? Itd make it easier to hypothesize about possible effects of mph and cocaine analogues. After what Nagelfar posted i starter thinking that mph is like a cross between amp and coke, even tho molecularly more similar to amp, pharmacologically tending towards Coke. Its got something to do with the carbomethoxy group right? How could mph be improved? I dont think one would want SERT affinity, itd add too much fiendiness i guess.

 

[sekio]

The dopamine transporter is a pretty damn complex protein (620 amino acids). Its amino acid sequence is known but its 3d structure has only been predicted [ref].

 

[atara]

The success of HDMP-28 suggests that the benzofuran-5-yl "-enidate" should have similar effects with a less scary metabolic profile. 5-APB is more serotonergic that 6-APB, so we'll go with that

 

[Nagelfar]

After what Nagelfar posted i starter thinking that mph is like a cross between amp and coke, even tho molecularly more similar to amp, pharmacologically tending towards Coke. Its got something to do with the carbomethoxy group right? How could mph be improved? I dont think one would want SERT affinity, itd add too much fiendiness i guess.

SERT affinity seems to have *less* fiending than pure DAT affinity, was my thought from literature I've read. Upping SERT takes away the "more-ishness" of dopaminergics.

& molecularly it's closer to coke too, not just pharmacologically; that's what I meant to prove by the above 3D overlay (cocaine has more affinity for SERT because the benzoyloxy is longer than the phenyl, HDMP-28 has the naphthyl to accomplish this, and CFT has a fluorine to do the same)

 

[Dresden]

desmethoxy-(oxy or hyrdro)codone. [oxycodone or hydrocodone with the aromatic methoxy replaced by a hydrogen atom]

roi,
I've thought of that one too, more than once.

 

[Nagelfar]

Using the highly potent 3β-alkylphenyltropane cocaine analogues (which are cocaine analogues proper & not phenyltropanes, despite the "-phenyltropane" in the same, the longer alkylphenyl's are classed, by S. Singh and other specialists, in with the benzoyloxy's) I made a cross between 224e (the most potent of that lettered series; compare; "cinnamoylcocaine") with 224d & the usual oxygenation of the "coke original formula" (dumb humor; that is to say: authentic cocaine) and I get this:

It just looks sterically strong somehow. ;-P

 

[atara]

That molecule doesn't exist -- keto-enol tautomerism always favors the keto, except in a or 1,3 dicarbonyl.

 

[Nagelfar]

I have a habit of doing that, that's what the "tongue in cheek" about it being "strong" was all about. (usually unstable)

-- keto-enol tautomerism always favors the keto, except in a or 1,3 dicarbonyl.

Would it work without the oxygen, then?

…

I have more faith in this one, a mixture of four cocaine analogues:

It's a combination of about every type of substitution/modification (except the 6/7 position ones) including the most efficacious among those being:

(remember the lower the number the higher the affinity)

185c (DAT displacement of WINcomp. 35428 binding @ 25 ± 4),
220c (inhibition of mazindol binding @ 120 ± 10 {cocaine is only 280 ± 60} and dopamine @ 160 ± 10 {again coke is only 320 ± 10}),
196n (DAT disp. of WIN 35... @ 61 ± 6 {cocaine @ 89 ± 4.8}) & finally,
224e (IC50 of cocaine binding @ 2.10 ± 0.04 {cocaine @ 101 ± 26} dopamine @ 138 ± 9 {cocaine comparison @ 209 ± 20})

...of course, may it be noted, all of them together doesn't mean synergistic effects, but some complete unknown variable that could be anything (even nonfunctional at MAT), QSAR is so very odd in that way.

 

[Pomzazed]

ACK ACK ACK

Why those functional group? It looks like a permanent poison!
Sulfonimide-ISOCYANATE ! (Really?) This looks like it instantly forms covalent binding?
Bromoacetamide moeity? (the bromo is event at the reactive alpha-position regarding the carbonyl)