I Like to Draw Pictures of Random Molecules

[crmt28]

Orphenadrine is an anti-cholinergic with additional NMDA antagonism and norepinephrine reuptake inhibition. Looks pretty interesting. It's Diphenydramine with an additional methyl group.

I wonder if removing the ethanolamine group could turn it into a pure NMDA antagonist. It would look pretty similar to Ephenidine.

Close the ring and it turns into a possible stimulant?

 

[N0 W4RN1NG]

Cool idea, I am not sure if the last one would have stimulant activity though. The molecule is now constrained in the wrong shape, I believe...I could be wrong of course.

Further modification of that last one may lead to Mu affinity though!

 

[Nagelfar]

WP page made for "FAUC50", 'dopamine native-headed' example re-drawn and added. Thanks!

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297708/figure/F6/

Generic pharmacophore for biogenic amine transporter ligands. Note that transportable substrate ligands exhibit size constraints defined by the red circle. Functional groups attached to the nitrogen, α-carbon or phenyl ring that extend beyond the “edge” of the pharmacophore will generate partial substrates, transporter blockers or be inactive.

This goes with the above, and is interesting.

I suppose a good observation to keep in mind for the substrate-terminus rule is: two methylene units above and below the dimension of the phenyl-to-amine, and three methylene units parallel in front and behind the phenyl and amine.

 

[DotChem]

Not what you may be thinking.. actually a potent opioid with kappa selectivity. It has no GABA-ergic!!

Tifluadom

Tifluadom^[1] is a benzodiazepine derivative with an unusual activity profile. Unlike most benzodiazepines, tifluadom has no activity at the GABA_A receptor, but instead is a selective agonist for the κ-opioid receptor.^[2] In accordance, it has potent analgesic^[3] and diuretic^[4] effects in animals, and also has sedative effects and stimulates appetite.^[5][6] While tifluadom has several effects which might have potential uses in medicine such as analgesia and appetite stimulation, κ-opioid agonists tend to produce undesirable effects in humans such as dysphoria and hallucinations, and so these drugs tend to only be used in scientific research. Dysphoric effects are similar to those seen when using other κ-opioid receptor agonists like pentazocine and salvinorin A.

wonder if the structure can be tweaked to a MOR selective eg the 7 or 8-OH analogue!

 

[Pomzazed]

^ So interesting about the above one, including the furan analog (instead of thiophene), Lufuradom.

 

[Nagelfar]

Dopamine agonists? (Looking at existing ones, Alentemol is interesting, selective dopamine autoreceptor agonist? Didn't think you could selectively single out autoreceptors!)

 

[Midnight Sun]

Not what you may be thinking.. actually a potent opioid with kappa selectivity. It has no GABA-ergic!!

Tifluadom


wonder if the structure can be tweaked to a MOR selective eg the 7 or 8-OH analogue!

well, it's not-so-vaguely reminiscent of tianeptine... which as we all probably know hits mu and delta. maybe start there?

 

[white55]

A benzo with no gaba activity? Think I'll pass.

 

[Nagelfar]

A benzo with no gaba activity? Think I'll pass.

There're many of them. Benzodiazepine is a structural name, not a functional one; though people use "GABAergic" and 'benzo' almost synonymously. The 2,3-benzos are without GABA function. GYKI-52,466 is an AMPAkine and glutamine receptor antagonist. Whereas GYKI-52895 is a dopamine reuptake inhibitor a la cocaine. Talk about different functional profiles.

 

[white55]

i'd rather have some of these

http://imgur.com/a/zUsdg

 

[Solipsis]

Something about pieces of land in vietnam.... waaaay too random, dude

I wonder if this is interesting as RC:
https://en.wikipedia.org/wiki/Dexanabinol

Talking about another drug in disguise :D

Yeah not the purpose of this thread but I wouldn't have a clue where to even modify it for shits and giggles.. it doesn't even have an amine function, does that even bind to the PCP site? I bet it doesn't trap shit.

 

[aced126]

The molecule might not be binding to the PCP site on NMDAr. It could be binding to the glycine or glutamate site.

 

[Nagelfar]

Something about pieces of land in vietnam.... waaaay too random, dude

I wonder if this is interesting as RC:
https://en.wikipedia.org/wiki/Dexanabinol

Talking about another drug in disguise :D

Yeah not the purpose of this thread but I wouldn't have a clue where to even modify it for shits and giggles.. it doesn't even have an amine function, does that even bind to the PCP site? I bet it doesn't trap shit.

If the "unnatural" isomer both of certain cannabinoids and of morphinan opioids (both phenanthrene) can be NMDA antagonists, how come we don't see a lot of cannabinoid/opioid dual-action compounds?

 

[roi]

 

[Solipsis]

If the "unnatural" isomer both of certain cannabinoids and of morphinan opioids (both phenanthrene) can be NMDA antagonists, how come we don't see a lot of cannabinoid/opioid dual-action compounds?

The probable answer is mentioned 2 times there are several binding sites on the NMDAr with apparently in some ways a similar pharmacophore but with probably quite different tolerances for modified substitution on ligands for them (or maybe less than we think, when we discover nitrogen-free PCP site antagonists).. I guess that serves the role to have two (or more) very similar endogenous neurotransmitters being able to regulate different processes on a receptor complex.
https://en.wikipedia.org/wiki/Neboglamine is positive allosteric modulator on (near?) the glycine site and I am seeing similarities with the previously mentioned dexanabinol. So it appears that opioid-like NMDA antagonists we know of bind to the PCP site and cannabinoid-like NMDA antagonists (or at least this one example) to the glycine site.
[edit: just checked and dexanabinol doesn't even bind to the glycine or glutamate site 'normally' but close, so I guess also allosterically - I think the arguments still all stand]

Trying to find a hybrid while sometimes possible, can often be frustrated by the fact that the compromise between what are actually different mechanisms is unacceptable.

Finding a good ligand for one site is hard enough, but finding one that satisfies two sites is freaking challenging like composing baroque counterpoint. Maybe first practice by secretly getting married twice and raising two families.

Also:
Dexanabinol is mentioned on the 'Cannabis cures cancer' facebook page, lmao sure take the credit

 

[Nagelfar]

but finding one that satisfies two sites is freaking challenging like composing baroque counterpoint. Maybe first practice by secretly getting married twice and raising two families.

I love J. S. Bach, and my great grandfather was a bigamist. So I'll find it...

 

[Nagelfar]

Triple covalent; but that napthyl-5′ acetyloxy just kills me. That's the clincher. Gotta be awesome.

 

[DotChem]

oops wrong thread..

 

[Nagelfar]

Check out that crazy ring formation on this cocaine analog! I think I'm going to have a cubism fetish again for a while. ;-P

 

[aced126]

Check out that crazy ring formation on this cocaine analog! I think I'm going to have a cubism fetish again for a while. ;-P

Has this been made? Can you post a source if so?