Optimizing molecules steric conformation w/ low energy process to prep. prior to RoA:

[Nagelfar]

Is the thread title a feasible endeavor? Allow me to clarify / elaborate using troparil as an example (the parent compound of a class of drugs with which I am quite familiar)

I made the above to correspond to a 3D animation (linked here, click to see) foot-notated so to qualify that its OMe on the carbmethoxy was "shown in an unfavorable conformation" for maximal stimulant potency as a ligand for DAT (e.g. the methyl had to be on the opposite oxygen and that methyl itself was supposed to face outward away from the body of the molecule. i.e. the 3D animated gif (& topmost image here posted) has its methyl on the 2 position ester as distal (from its phenyl) & cis; but for it to bind with most efficacy it has to be trans & proximal (i.e. nearest to but facing up and away from) to the phenyl group.

I know molecules, insofar as this degree of change is concerned, rotate and move with some level of fluidity and freedom of motion (without degrading or deteriorating by way of its labile nature) back and forth; but I presume it has to take some energy to get it aligned to one specific conformational orientation. Is there a possibility of a preparation, chemical of some sort (theoretically, not asking for specifics to make it clear) like had in synthesis, quenching, refluxing etc., that would put a pertinent functionality of a given molecule; in this instance troparil's carbmethoxy, in a position / shape where it'd stay (not like hard isomerism where the constituents of the molecule differ in an absolute way) via some amount of low energy but enough to keep it there, so upon administration the entire content per weight of the substance is aligned in its optimum ligand shape, boat formation, chair formation, etc. and though likely to change in some small degree on its way to the brain and site, has a high yield (95% or so) conformed in its best subjective facing to hit the receptor on its onset (smoked, IV'd) to make quickening of onset that can be noticed?

 

[serotonin2A]

The only way to do what you are asking is to constrain the groups into bridged/tethered structure that is more rigid. But that involves changing the structure of troparil.

In theory, if it was possible to do what you are asking, that would increase the potency but it wouldn't change the speed of onset.

 

[aced126]

^^Yep, synthesize a rigidified derivative. You'll find something pretty similar to what you're thinking about on my post in random mol thread pg 124.

If not rigidified, the molecule will normally adopt the lowest energy conformation and likely bind with its target in a conformation close to its lowest energy conformation.

 

[Nagelfar]

What about systemic delivery via a particle-scaffold such as a cyclodextrin? Would it remain within the realm of possibility for one to be so constructed as to keep a molecule to which the carrier nonparticle was specifically designed to constrain it (in other than would be its least energy state outside of which) until it reaches the place of binding?

Perhaps a solute vehicle (same concept as a lipid emulstion vehicle except for a suspension or solution other than basic water but analogous enough to water to not display a toxic effect with administration) that maintains the drug in a different than least energy state otherwise that is a more consistently optimum conformation than surrounding bodily plasma concentrations and would not allow for escape by diffusion into the body's own environs without that as its surrounding exogenous carrier-pocket and can remain with it until reaching the target site where its Ki strength would alone be suffient to penetrate or disassociate enough from its "bubble" (or even stay within it until the binding site residues and does not keep it from associating) to improve upon its binding?

Perhaps something along the lines of a protonated form that alters its least energy state continually throughout membrane diffusion until reaching the site that plays the part of acceptor to its ligand functionality?

 

[serotonin2A]

I don't understad the goal you want to achieve. Any complex you could form would have to dissociate before binding occured, leaving you with the free ligand in solution.

 

[Nagelfar]

I don't understad the goal you want to achieve. Any complex you could form would have to dissociate before binding occured, leaving you with the free ligand in solution.

I posited alternatives to requiring dissociation in the above in my second two propositions. I think it's pretty straight forward and you have the gist of it from your response above.

 

[serotonin2A]

I posited alternatives to requiring dissociation in the above in my second two propositions. I think it's pretty straight forward and you have the gist of it from your response above.

I obviously read what you posted, but none of the alternatives you proposed would bypass the need for the ligand to disassociate prior to binding to DAT. Even if you somehow found a scaffold that could bind to DAT and then release the free ligand directly into the binding site, there still would be an intervening transition step where parts of the ligand would be free to rotate.

That is why chemists have to go through the trouble of making tethered ligands.

 

[belligerent drunk]

As serotonin2A said, it's not possible. Basically it is possible to change what conformation a molecule adopts with different solvents. For example, 2-chlorophenol will have its phenolic hydrogen face different directions depending on how good of a hydrogen bond acceptor the solvent is. However, what you're proposing is restricting the whole population of molecules to a single energy state (the one conformer you want), which in itself is hardly possible, and then hoping that the energy distribution of said population goes unchanged when in solution (where countless interactions occur leading to changes of energies of single molecules, and thus changes in conformations of said molecules).

Again, it would be possible to constrain the molecules to a certain non-lowest energy conformation by using a complex, but it would have to dissociate from it before it could bind to whatever you want it to bind to, and that would still mean it has time to change conformations in solution.

 

[Nagelfar]

I obviously read what you posted, but none of the alternatives you proposed would bypass the need for the ligand to disassociate prior to binding to DAT. Even if you somehow found a scaffold that could bind to DAT and then release the free ligand directly into the binding site, there still would be an intervening transition step where parts of the ligand would be free to rotate.

That is why chemists have to go through the trouble of making tethered ligands.

I figured my second two would?

As serotonin2A said, it's not possible.
...
Again, it would be possible to constrain the molecules to a certain non-lowest energy conformation by using a complex, but it would have to dissociate from it before it could bind to whatever you want it to bind to, and that would still mean it has time to change conformations in solution.

OK my second two were not about the "scaffold" or anything to disassociate from; would a homologous-to-H₂O solution have to adopt the microenvironmental conditions nearest the ligand site, I have read that the basic nitrogen of DARI drugs @ MAT when binding possibly undergo protonation and change in that alkaloid 180 degree shift from lipid solute to water solute, but it was tentative type talk (much as this)

 

[belligerent drunk]

Without giving it much thought I see a fundamental problem with your idea. In order to force a part of a molecule to adopt an otherwise unfavorable conformation you have to somehow affect it, e.g by binding it to a complex in which the previously unfavorable conformation becomes the most favorable (enzymes do this in some cases), but this automatically means that said part of the molecule is already in interaction with something, so it is not "free" to bind to your target.

 

[clubcard]

I think it's the wrong isomer at the benzene junction.

 

[Nagelfar]

Without giving it much thought I see a fundamental problem with your idea. In order to force a part of a molecule to adopt an otherwise unfavorable conformation you have to somehow affect it, e.g by binding it to a complex in which the previously unfavorable conformation becomes the most favorable (enzymes do this in some cases), but this automatically means that said part of the molecule is already in interaction with something, so it is not "free" to bind to your target.

A bit of the "measurement paradox" on a Newtonian scale here, then?

I think it's the wrong isomer at the benzene junction.

It should be correct. Beta for both esters is the same as R-coke. Benztropines and others are alpha there, though. So perhaps that's what you're remembering.

 

[belligerent drunk]

A bit of the "measurement paradox" on a Newtonian scale here, then?

Lol, perhaps if you want to call it that.

 

[clubcard]

A bit of the "measurement paradox" on a Newtonian scale here, then?



It should be correct. Beta for both esters is the same as R-coke. Benztropines and others are alpha there, though. So perhaps that's what you're remembering.

Look at the isomer in cocaine.

 

[serotonin2A]

Look at the isomer in cocaine.

I think CC and Nagelfar are talking across each other on this one. Technically the structure is correct -- a wedged bond denotes a bond pointing upward through the page -- even if Nagelfar actually drew it pointing down. It looks really weird, but I think it technically is the right isomer.

 

[clubcard]

Well, I stand corrected - apologies. Adding a ...H would make it very clear

 

[serotonin2A]

Well, I stand corrected - apologies. Adding a ...H would make it very clear

I think a better solution would be for Nagelfar to draw the pictures in a less confusing way.

 

[Nagelfar]

I think a better solution would be for Nagelfar to draw the pictures in a less confusing way.

I wouldn't be Nagelfar, then. ;-j ;-P

(EDIT: P.S., go to "chemicalize.org" and type in "troparil" and hit *enter*, that's the way Marvin Beans draws it, not me)

Well, I stand corrected - apologies. Adding a ...H would make it very clear

EDIT#2: This better guys?:

 

[clubcard]

That's nice and clear. IUPAC->image is something this board NEEDS.