I Like to Draw Pictures of Random Molecules

[aced126]

^ Synthetically the difference between phenyltropanes and those 4-aryl-3-carboalkoxypiperidines is huge IMO. I don't know if there are any short-acting phenyltropanes, but if we limit ourselves to the simplest 2-carboalkoxy-3-aryltropanes, they are all long-acting stimulants which most possibly makes them poor recreational drugs which combined with not necessarily cheap common substrate makes them not attractive as "RC's".

The piperidines might as well be more like SSRI/SNRI antidepressant with little recreational value, they might have been tested in small groups of volunteers and turned out not interesting.

They are only long lasting because of loss of ester functionality. Bridge the piperidine with the aryl ring with an ester to reduce half life.

Compared to cocaine itself, the syntheses of these piperidines would be much, much easier. They look quite reasonable to synthesise and the data for some of them makes it look much more potent than cocaine itself.

 

[Nagelfar]

they are all long-acting stimulants which most possibly makes them poor recreational drugs

If they were any good, we would probably already know by now.

They are only long lasting because of loss of ester functionality. Bridge the piperidine with the aryl ring with an ester to reduce half life.

What aced said is true; there is no reason why not to believe these piperidines should be any different than Troparil, which has been colloquially reported as "disappointing"

Cocaine analogs show a lot more potential for this reason. The C1 substitutions being the newest in the interesting additions:

^3betaStyrene-OrthoAcetoxy-C1Phenyl-"Cocamentholene"

 

[Dresden]

That one looks as possibly dissociative as fuck.

 

[sekio]

it looks to have too much stuff everywhere to bind to anything.
huge gif alert:

NSFW:

 

[Nagelfar]

That one looks as possibly dissociative as fuck.

it looks to have too much stuff everywhere to bind to anything.

Thanks for that animation sek. (From everything I know and have studied, however, it has enough room at all the proper spaces to fit nicely at DAT; the C1 group substitution was originally on a C3 benzoyloxy derivative, and the styrene alkylphenyl is the same length in angstroms, etc.)

 

[Pomzazed]

The bridge is important - if you lose it, almost all potency is lost iirc.

Then why alkylphenidates work?

 

[Dresden]

A study found this

to be a stimulant but not a psychedelic. No word on possible neurotoxicity.

 

[aced126]

Then why alkylphenidates work?

Alkylphenidates have different connectivity to cocaine. Try to overlay to conformations of methylphenidate and cocaine. It doesn't seem to me like a good overlay. I've always wondered why alkylphenidates and cocaine have been compared structurally. They might both have the same effect at DAT, but they are structurally quite different.

 

[Nagelfar]

Try to overlay to conformations of methylphenidate and cocaine. It doesn't seem to me like a good overlay. I've always wondered why alkylphenidates and cocaine have been compared structurally. They might both have the same effect at DAT, but they are structurally quite different.

beta-CFT (the prototypical PT; the fluoro makes it closer to coke @ SERT than Troparil) with methylnaphthyldate (the naphthyl making it, similarly, closer to cocaine @ SERT than MPH)

Looks like a *perfect* *overlay* to me.
Given below singly:

which follows:

^(despite cocaine being longer at the aryl-linkage; greatening serotonin transporter affinity in contrast to CPT & MPH.)

 

[aced126]

beta-CFT (the prototypical PT; the fluoro makes it closer to coke @ SERT than Troparil) with methylnaphthyldate (the naphthyl making it, similarly, closer to cocaine @ SERT than MPH)

Looks like a *perfect* *overlay* to me.
Given below singly:

which follows:

^(despite cocaine being longer at the aryl-linkage; greatening serotonin transporter affinity in contrast to CPT & MPH.)

Binding is very intricate.

The way you have overlayed it, the 2 aromatic systems are orthogonal to each other. The two compounds will then pi stack differently with their residues, altering affinity. Not to mention the carboxylates and amines are pointing in different directions.

 

[Nagelfar]

Binding is very intricate.

The way you have overlayed it, the 2 aromatic systems are orthogonal to each other. The two compounds will then pi stack differently with their residues, altering affinity

Yes, they freely spin in their respective mechanics, that is I presume so the two aryls can be seen as distinct in the 3-dimensional overlay between the two different compounds. It shows more intricacy doing it in three dimensions. As for pi-stacking, look at the amount of things and alterations can be given to the carbmethoxy, and even the hybrid compound DMNPC is half way between MPH and PTs/cocaine:

I didn't make that overlay, however, BTW. I am not wanting to get into a squabble over this; earnestly and in legitimate curiosity to learn, be proven wrong, etc., how would you overlay them as they "would" then? What are the intricacies to which you are referencing that make my overlay given over to tentative plausibility?

Not to mention the carboxylates and amines are pointing in different directions.

in the 2D separate images you mean? Flip them around, the stereochemistry isn't even indicated (I am not trying to be discreet and gloss over a similarity that is blatantly lacking if shown in a more specific rendering of some kind) Otherwise, the carboxylate/carbmethoxy group spins & rotates freely too:

As for the amine: the nitrogen lone pair orients forward or backward as it isn't constrained in either of those compounds (cocaine, MPH or their two analogues given), in fact it alternates between one or the other depending on whether it is binding to DAT or SERT (in front and back bridged phenyltropanes, however, it is constrained; not in any pictured in my previous post, however; but this is known to heighten selectivity) this has to do with orbital hybridisation.

A study found this

to be a stimulant but not a psychedelic. No word on possible neurotoxicity.

Not to overlook this, do you have the study to cite Dres? Quite interesting.

 

[adder]

beta-CFT (the prototypical PT; the fluoro makes it closer to coke @ SERT than Troparil) with methylnaphthyldate (the naphthyl making it, similarly, closer to cocaine @ SERT than MPH)

I suppose that they can bind in a very similar manner no matter whether the most stable conformations of both have all major functionalities overlaid or not, the interaction at the receptor can surely heavily alter the conformation so that ring flip of ~90 degrees around the C-C bond may not be a problem at all. The problem is that simple programs that make corrections for the most stable conformations do so for isolated molecules or a set of several molecules at best. Our deliberations here on utilizing the known SAR's and/or attempting to connect the dots and extend them unfortunately lack a major component of the information which is receptor models. So it's always just pure assumptions that never get tested. Still, even quantum chemistry calculations that seemingly take into account a lot of factors often fail to represent what happens in reality as it's always based on approximation.

 

[DotChem]

This is a big finding and I'm surprised I didn't know about this. This stems a new set of DRIs - why haven't more of these been made by RC suppliers?

Actually, there are more like selective NDRI with the naphthyl beeing SNDRI (check out their SAR papers). I guess the reason those were not pursued as RC markets is they are more closer to methylphenidate in term of effect but only more expensive. The easier synthetic route is via arylation of arecoline (extracted from some nuts growing in Asia). But arecoline itself is not really cheap so there is no point

As for half life, the carboalkoxy-aryl-piperidines are actually pretty different from the phenyl tropanes. Nocaine T1/2 is ca 5 hours while some the beta-carbethoxy-phenyl tropane have a T1/2 of up to 2 WEEKS!!! (can you imagine!!

NB: according to original paper, rats trained to self-administer cocaine can't tell the difference between Nocaine and Cocaine lever..whcih is interesting because the same paper claim..." the compound was found to substitute for cocaine in animal models while having significantly less abuse potential itself."

In fact, the first

could be dubbed 3,4-dihydro-4-(4-methylphenyl)-arecoline!

Yes actually, they were all made from arecoline. at least the trans.

 

[DotChem]

..Our deliberations here on utilizing the known SAR's and/or attempting to connect the dots and extend them unfortunately lack a major component of the information which is receptor models. So it's always just pure assumptions that never get tested...

Actually we do: the crystal structures of cocaine, dopamine, beta-CFT, dichlorophenethylamine, methamphetamine and dopamine bound to transporter DAT are all available (check it out on pubmed). That is as close as it gets from having all the information needed to "connect the dots".

The one issue with DAT binding to substrate (or inhibitors) though is that it required Na+ binding first for the substrate to be able to bind. In the absence of Sodium, transport is drastically diminished. Binding of Na+ induce major changes in the conformation of the DAT protein that can accommodate binding of DRIs or dopamine substrate by exposing the binding site. The site thus generated upon Na binding that can accomodate DRI ligands (or DA substrate) is pretty flexible so diverse molecules can bind without necessary having similar geometry. I mean diverse up to a point. That's why Cocaine, MPH or METH can all bind and block the substrate from access. Very very different from these yet are selective incredebly potent DRIs like Mazindol or 3C-PEP with a structure totally different from the tropanes or the phenethylamines.

 

[DotChem]

more on Nocaine: according to original paper, the carbalkoxy-phenyl piperidines such as Nocaine are selective NDRI unlike cocaine, they much closer to MDPV or similar cathinones. They would certainly make potent aphrodisiac if anything .. talking about selective NDRIs aphrodisiac, these compounds from Denmark (big pharma!) were claimed as potent and selective NDRIs about 100x more potent than MDPV (at NET and DAT; ca 100,000x more than cocaine) with less (100s times less) serotonergic (X, Y =Cl or Br). If what they claim in the patent is correct, they may be he next flakka!

they look strangely similar to U4 opioids with the the amide inverted !!

Edit: read 10x more potent than PVP. The reported IC50 values claimed in this patent are:
Monoamines Uptake Inhibition IC50(uM):
SERT = 0.37 ; DAT = 0.0040 ; NET = 0.0031 for the dibromophenyl above

For alfa-PVP IC50 (uM)
SERT = 2.78 ; DAT = 0.052 ; NET = 0.028

 

[Dresden]

Nagelfar,

No, unfortunately, I don't recall that citation. I think the study was from the early '60s, though.

 

[adder]

Actually we do: the crystal structures of cocaine, dopamine, beta-CFT, dichlorophenethylamine, methamphetamine and dopamine bound to transporter DAT are all available (check it out on pubmed). That is as close as it gets from having all the information needed to "connect the dots".

Yes, I know you can find those in articles, and not only for DAT, I came across such images of ligands bound to opioid and serotonin receptors, they are fun, but still you can't invent a molecule and put it into a model, and be sure it fits or have electronic properties as you think it does. With good imagination you can imagine how a close structural analogue might bind, but even for a not so distantly related molecule it becomes too little. I'm wondering if making a model of a given receptor to be able to use it in computations would be a costly thing to do if you had access to a biochemical lab. Certainly, a fast computer would be necessary in the latter phase, but it's interesting if simply experiments necessary to build a model would be expensive provided that you had the know-how to do it. I would guess the most expensive phase of new-drug research is the synthesis of potential ligands if it gets complex and requires expensive reagents.

Quite far from the current topic discussed, but here's an interesting article comparing affinity of intrinsic activity of analogues of buprenorphine, you could say, with t-butyl group swapped for different alkyl and cycloalkyl groups with different stereochemistry at C20.

 

[Nagelfar]

Binding is very intricate.

The way you have overlayed it, the 2 aromatic systems are orthogonal to each other. The two compounds will then pi stack differently with their residues, altering affinity. Not to mention the carboxylates and amines are pointing in different directions.

Also aced, have you read the DAT crystrallographic studies that show most DAT ligands bind to 10—12 loci, but cocaine & methylphenidate both bind to the 9—through—11 loci? (all seem to similarly bind to 1 & 7 in addition to that divergence . The major difference between them seem to be their respective 'enthropy of binding': cocaine —5.6 kcal/mol & methylphenidate —25.5 kcal/mol. Ref. Bonnet, J.-J.; Benmansour, S.; Costenin, J.; Parker, E. M. ;Cubeddu, L. X. J. Pharmacol. Exp. Ther. 1990, 253, 1206)

Also check out: Blough, Bruce E.; Keverline, Kathryn I.; Nie, Zhe; Navarro, Hernán; Kuhar, Michael J.; Carroll, F. Ivy (2002). "Synthesis and Transporter Binding Properties of 3β-[4'-(Phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2β-carboxylic Acid Methyl Esters: Evidence of a Remote Phenyl Binding Domain on the Dopamine Transporter". Journal of Medicinal Chemistry. 45 (18): 4029–37. doi:10.1021/jm020098n. PMID 12190324

^Because there is apparently a domain *beyond* (but skipping, apparently, DAT loci) 12, that cocaine and possibly MPH analogs can reach: As below:

So making a cocaine analog of the above phenyltropane:

^the way the benzoyl oxy spins might gimp it in this context, at least increased flexibility might make it not as potent.

 

[Nagelfar]

[η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

anyone able to draw the above IUPAC / following images in three dimensions, ball and stick rotating, i.e. animated, rendering?

21b:

..I was also theorizing to myself, might TACD just decrease in length the short actingness of IV cocaine, making it more prone to habituation and more compulsive / addictive?

 

[Solipsis]

I like to draw molecules of random pictures