I Like to Draw Pictures of Random Molecules

[Nagelfar]

^anyhow, I am believing the above would have anti-chlorinergic effects, like tematropium & tropatepine, possibly, but the cyclopentane is smaller so perhaps not.

2-Thiophene with the length para addition that is between RTI-430 & RTI-298 (para of benzene equals: –C≡C-CH2Ph) which has the distal extra binding site for dopaminergic affinity.

e.g. between this:

52 ± 12.8 DAT


And this:

1.82 ± 0.42 DAT

 

[EP-11]

^anyhow, I am believing the above would have anti-chlorinergic effects, like tematropium & tropatepine, possibly, but the cyclopentane is smaller so perhaps not.

Thanks for the insight

 

[DotChem]

..something not as short acting as MPH but not as long as DPMP. Even the non-desoxy version of that seems way too lipophilic to me and not particularly metabolizable...The enol ethers would be messed up in the stomach though? That wouldn't be good..

Would amides bioisosteres work? like this and similar NHEt NMe2...etc etc

Increased half-life relative to MPH but not too much like pipradol types? Amides are more metabolically stable than esters. eg you go from anesthesic Procaine (T1/2 ~ 84 seconds in plasma) to procainamide (T1/2 ~ 3h). Plus they may have faster onset because less lipophilic .. and/or increased binding affinity to the transporter: with a little luck, the extra NH might picks up a hydrogen-bond or 2 with the receptor.. but who knows?

PS: IMHO there is no point for bioisosteric replacement of MPH except maybe legal issues perhaps. The reason is that they'll pretty much have to be synthesized from MPH anyway so ended up more expensive with little advantage compared to MPH esters ET or iPr..etc Unless they may be easier cheaper route !

 

[EP-11]

 

[Nagelfar]

highest potency 'restricted rotational analog' of methylphenidate, with elements (aryl-planar ring unit, deoxygenated restricted-carbmethoxy) made to mimic fentanyl.

Another "Ritalin/Fentanyl" hybrid:

i.e.

+

 

[Nagelfar]

^Asymmetrical non-planar arene area caused increased binding in the eta-6 coordinated chelated phenyltropanes: using the bulk of those sigmaergics recently elucidated as the arene unit (one was highly dopaminergic, I used that one as a base, though it wasn't the boxed cyclopentane that did it, I reckon) in cocaine, this looks awesomely poignant even in inactive, profound even.

cf.

Various fluoxetine + amphetamine hybrid/intermediates:

 

[Dresden]

You can't have aminals and hemiaminals. It's really simple. If the structure has an N-C-O, then it's probably not going to exist.

There really aren't many exceptions, either.

 

[DotChem]

U-4X

 

[Nagelfar]

You can't have aminals and hemiaminals. It's really simple. If the structure has an N-C-O, then it's probably not going to exist.

There really aren't many exceptions, either.

I always draw 'em without thinking 'bout it when throwing together "hybrids", gotta watch that tendency better.

More cyclopentane-cage-arene-substituted phenyltropanes:

These are attested to hemiaminals that work.

 

[sekio]

^ sup dawg, we added a ring system to your ring system 'cause i herd you like ring systems

 

[Nagelfar]

^ sup dawg, we added a ring system to your ring system 'cause i herd you like ring systems

sekio gets it. ;-j

 

[Nagelfar]

^Diclofensine + Quinolizidine MPH analog structure

 

[Dresden]

This is inspired by a cocaine analogue that Nagelfar brought up. If it's anything like PMA, then that's no good, but who knows?

 

[EP-11]

Mesocarb analogues

 

[Nagelfar]

This is inspired by a cocaine analogue that Nagelfar brought up. If it's anything like PMA, then that's no good, but who knows?

"Like" subjectively, and "like" structurally, can be worlds apart, thank goodness. But yes those thiophene DRIs should be looked at in more detail.

 

[Nagelfar]

^OK:

DAT ligand (Mazindol) displacement: 0.14 ± 0.07
DA uptake displacement: 0.31 ± 0.09

+

DAT ligand (RTI-55) displacement: 0.03 ± 0.01

compare (note all naphthyls are 2-naphthyl, 1-napthyl is across the board higher-numbers/lower-affinity):

DAT ligand (RTI-55) displacement: 0.115 ± 0.021

DAT ligand (RTI-55) displacement: 0.28 ± 0.11

DAT ligand (beta-CFT) displacement: 0.51 ± 0.03
DAT ligand (cocaine) displacement: 3.32 ± 0.08
DA uptake displacement: 3.53 ± 0.09

sup dawg, we added a ring system to your ring system 'cause i herd you like ring systems

Now that I think about it, that inspired this:

Spirocyclic Trishomocubane Tropane, or Polyspirocyclopentacagecaine

 

[Dresden]

Super dopamine reuptake inhibitor

 

[Nagelfar]

Super dopamine reuptake inhibitor

Just a para-thiophene MPH. Remember, benzyl cocaine/phenyltropane works but benzyl ritalin doesn't, so it might not stick in the same.

EDIT:

example:

Binding: 885 ± 18 IC₅₀
Uptake: 1020 ± 52 IC₅₀

Binding: >5000 K_i

(of course K_i vs. IC₅₀, and different displacement, ligands across different data sets shouldn't be too indicative, but generally in the same class I've found they balance if comparing just two and not three for which of the two are better)

 

[EP-11]

What would this be like

 

[Dresden]

No one knows what that would be like without making and trying it.