The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

[DotChem]

Why does diastereomeric recrystallisation work?

What are the molecular reasons behind why 2 enantiomers can't be separated with chromotography but 2 diastereomers can?

It boils down to solvation: the solvation shell around a diastereoisomer pairs is different for each of the diastereoisomer. So their physical properties including their Rf is different. And also because of that, they crystallize under different conditions hence they can be separated by selective fractional recrystallization.
On the other hand, solvation of an enantiomeric pair is the same for both enantiomers. So their physical properties will be the same in solution (ie for Rf: the eluting solvent and the stationary phase can't tell the difference so to speak). UNLESS the solvent used is chiral in that case the solvation will give 2 ( L(+)S(+) and L(-)S(+) not 1 solvated entities (L(+)-S. Kind of like the non-covalent (VanderWaals only) complex equivalent of diastereoisomers! chiral compound solvated by chiral solvent or complexed by chiral chromatographic media. Hence the use of chiral stationary phase to separate enantiomers... does it make sense??

 

[aced126]

What are the molecular reasons behind why the solvation shell is different for 2 diastereomers but the same for 2 enantiomers?

 

[Pomzazed]

Ha aced,

Enantiomer: u have exact mirror image of left and right gloves, same mass and u cant separate by shaking the box.

Now u form a diastereomer pair, u tie each glove with left shoe only. Now this got a shape different (yo, solvation!)
A glob of "leftglove+leftshoe" is now different in space/shape requirement than "rightglove+leftshoe"

Make sense now?

 

[aced126]

Ha aced,

Enantiomer: u have exact mirror image of left and right gloves, same mass and u cant separate by shaking the box.

Now u form a diastereomer pair, u tie each glove with left shoe only. Now this got a shape different (yo, solvation!)
A glob of "leftglove+leftshoe" is now different in space/shape requirement than "rightglove+leftshoe"

Make sense now?

Enantiomers kind of have different shapes too, otherwise enantiomers of a compound wouldn't show wildly different pharmacological activity.

 

[DotChem]

What are the molecular reasons behind why the solvation shell is different for 2 diastereomers but the same for 2 enantiomers?

What do you mean by "molecular reasons"? The solvation shell ie the surface area (the solvent accessible area of the molecule) topography will be different because the relative position of the atoms in the diastereoisomeric pair is not the same. So the solvated forms will give physically different entities (ie relative positions of charged groups in the molecule, heteroatoms..etc will be different). And that will make them crystallize to a different crystal lattice or at different conditions. Or move at different speed in chromatograph media (Rf). Question of geometrical shapes actually! (see crystal lattice system here ).

On the other hand, the relative position of the atoms in an enantiomeric pair is the same. As far as the solvent is concerned. Not so for a POLARIZED ray of light!! The solvent approach, interact (vanDerWaals..salt.H-bond..etc) and solvate the molecule from its right side or its left side equally. So long as the solvent IS NOT chiral. So the shape of the "2" entities are the same. Kind of like those "ambidextrous" gloves where it doesn't matter whether the right or the left hand, the glove will fit, it can't tell a difference.

Another way to look at this is the 3-point model of biological binding with chiral drugs sp3 carbon: 3 point 3-D pharmacophore (L1 interact with P1 AND L1---P2 AND L3---P3) for optimum binding. L = pharmacophore group of the drug, P = corresponding interaction pocket at the protein binding site. Only 1 enantiomer of a chiral sp3 carbon can satisfy the 3-point interactions at the same time!! And that is because the environment in proteins and other biomolecules is most often not symmetrical. P1 P2 P3 arrangement in 3D.

 

[Pomzazed]

Aced, the above sentence is only true when environment is chiral. Like in biological system.
Enan hasnt got different shape, but they are flipped on other side (exact same shape)
But in chiral environment like receptor, these make difference.

What i stated is like you have a nonchiral (eg. Toluene) solvent/environment, then you dissolve racemic amphets fo example.
You cannot separate it with achiral ways cos they are so the same, (D-Amp, L-Amp)then you add ONE other compound with chirality
eg. Add L-Malic to it.
The "ion cage"(salt cage" structure of D-Amp/L-Malic and L-Amp/L-Malic is very different in shape thus solvation in toluene is difference, thus solubility, thus fractional crystallization is possible.

Let's say in achiral environment you cant distinguish the enantiomer by any means except light angle changing when pas thru it.
With more chiral environment (eg. Chiral HPLC column) the interaction for each enantiomer+chiralcolumnsurface will be diff so u can separate it.
With even more chiral-fixed environment like body, its no wonder why enan gives vastly diff pharma profile.

If still unclear ask out more i can try to answer (my english is bad, not main used language sorry for this)

 

[aced126]

Aced, the above sentence is only true when environment is chiral. Like in biological system.
Enan hasnt got different shape, but they are flipped on other side (exact same shape)
But in chiral environment like receptor, these make difference.

What i stated is like you have a nonchiral (eg. Toluene) solvent/environment, then you dissolve racemic amphets fo example.
You cannot separate it with achiral ways cos they are so the same, (D-Amp, L-Amp)then you add ONE other compound with chirality
eg. Add L-Malic to it.
The "ion cage"(salt cage" structure of D-Amp/L-Malic and L-Amp/L-Malic is very different in shape thus solvation in toluene is difference, thus solubility, thus fractional crystallization is possible.

Let's say in achiral environment you cant distinguish the enantiomer by any means except light angle changing when pas thru it.
With more chiral environment (eg. Chiral HPLC column) the interaction for each enantiomer+chiralcolumnsurface will be diff so u can separate it.
With even more chiral-fixed environment like body, its no wonder why enan gives vastly diff pharma profile.

If still unclear ask out more i can try to answer (my english is bad, not main used language sorry for this)

What do you mean by "molecular reasons"? The solvation shell ie the surface area (the solvent accessible area of the molecule) topography will be different because the relative position of the atoms in the diastereoisomeric pair is not the same. So the solvated forms will give physically different entities (ie relative positions of charged groups in the molecule, heteroatoms..etc will be different). And that will make them crystallize to a different crystal lattice or at different conditions. Or move at different speed in chromatograph media (Rf). Question of geometrical shapes actually! (see crystal lattice system here ).

On the other hand, the relative position of the atoms in an enantiomeric pair is the same. As far as the solvent is concerned. Not so for a POLARIZED ray of light!! The solvent approach, interact (vanDerWaals..salt.H-bond..etc) and solvate the molecule from its right side or its left side equally. So long as the solvent IS NOT chiral. So the shape of the "2" entities are the same. Kind of like those "ambidextrous" gloves where it doesn't matter whether the right or the left hand, the glove will fit, it can't tell a difference.

Another way to look at this is the 3-point model of biological binding with chiral drugs sp3 carbon: 3 point 3-D pharmacophore (L1 interact with P1 AND L1---P2 AND L3---P3) for optimum binding. L = pharmacophore group of the drug, P = corresponding interaction pocket at the protein binding site. Only 1 enantiomer of a chiral sp3 carbon can satisfy the 3-point interactions at the same time!! And that is because the environment in proteins and other biomolecules is most often not symmetrical. P1 P2 P3 arrangement in 3D.

Thanks both, I understand now.

 

[aced126]

Have polar CB1 agonists and/or antagonists that do not cross the BBB been reported?

 

[belligerent drunk]

^ I'm not very familiar with cannabinoid receptor ligands, but are there not any basic nitrogen-containing ones? Because if there are, then I imagine it would not be too difficult to make an alkyl quaternary salt of the compound, and that would limit its BBB permeability greatly.

 

[aced126]

^ I'm not very familiar with cannabinoid receptor ligands, but are there not any basic nitrogen-containing ones? Because if there are, then I imagine it would not be too difficult to make an alkyl quaternary salt of the compound, and that would limit its BBB permeability greatly.

That is what I was thinking as well. For example, here is rimonabant, a BBB-permeable CB1 inverse agonist: https://en.wikipedia.org/wiki/Rimonabant

https://en.wikipedia.org/wiki/Canna.../File:Metabolic_effects_of_CB1_antagonism.png

The diagram linked indicates a major mechanism of action of Rimonabant is through antagonising CB1 receptors in the hypothalamus region. However it also clearly depicts peripheral means by which it could act. And as we all know CB1 receptors are expressed densely throughout the brain, not really contributing to the drug's selectivity. This fact, maybe amplified by the drug antagonising mu receptors, could be the reason why some patients experience negative CNS effects while on this, like depression or suicidal thoughts. If a quarternary salt derivatives of Rimonabant could be evaluated, they may show promise in this respect.

Likewise, CB1 and CB2 agonists have been shown to have therapeutic potential in treating peripheral disorders like inflammatory pain, so developing impermeable agonists could gain easier approval if it does turn out to be beneficial.

 

[belligerent drunk]

The compound you brought up has 2 nitrogen centres, of which I imagine the hydrazide nitrogen would have the highest basicity/nucleophilicity, and I don't see any reason why it would be difficult to methylate that nitrogen to produce a quaternary salt and effectively make it only peripherally-active. I also don't think that adding a methylene bridge (N-CH2-H+ vs. N-H+) would affect its affinity for CB receptors significantly, unless there's a specific reason for that.

 

[DotChem]

Have polar CB1 agonists and/or antagonists that do not cross the BBB been reported?

...AM-6545 does not cross the blood–brain barrier to any significant extent, it does not produce these kinds of side effects[depression and sucidal thoights], but has still been shown to effectively reduce appetite and food consumption in animal studies....https://en.wikipedia.org/wiki/AM-6545

Basic idea was to increase hydrophilcity by replacing a CH2 of the piperidyl with a sulfoxide or a sulfone: increase dramatically polarity while retaining good binding since sulfoxide or sulfone are neutral. That prevent its crossing BBB while still antagonizing peripheral CB1Rs.

 

[belligerent drunk]

^ I think aced is asking for efficacious CB agonists that are non-CNS active, which is easily done by making the drug a methylated quaternary salt. I see no reason in making it a sulfoxide or sulfone, especially if it doesn't provide a charge.

 

[DotChem]

^ I think aced is asking for efficacious CB agonists that are non-CNS active, which is easily done by making the drug a methylated quaternary salt. I see no reason in making it a sulfoxide or sulfone, especially if it doesn't provide a charge.

agonists and/or antagonists that do not cross the BBB been reported?

.. but I am sure there must be CB agonists that do not cross BBB too. But you're right: adding a permanently charge group will prevent the molecule crossing BBB but you might kill receptor affinity in so doing. This probably the reason the authors choose a sulfone is so you still maintain CB1 activity! I don't know detailed SAR around CB1 ligands. But in general, quaternary ammonium salts with a positive charge may not like the binding site where the part of the Cannabinoid molecule beeing replaced is interacting. The site may be too lipophilic to accommodate a charged ammonium. ie higher desolvation energy..Unless the quaternary ammonium is located in some part of the molecule which is not involved in interacting with the receptor CB1R. Detailed SAR can tell that.. But yes of course it might work!

 

[belligerent drunk]

Typically binding occurs with a (partially) protonated quaternary amine salt, reight? Making it an alkyl quaternary salt will just decrease its BBB permeability, whereas its binding profile (a methyl group being not much different from a hydrogen as far as electronic structure is concerned) will be preserved - except its brain activity.

Methylating the nitrogen in the compound is both easier, and more logical than introducing sulfur moieties.

 

[Pomzazed]

^ That is not quite true for CB ligands.

Main interaction does not need the positively-charged species anywhere in the molecules which will destroy the activity.
Required pharmacophore for it is the
1) Two hydrophobic bulky region, one must be planar and one does not need to. (eg. Phenol region and polycyclic alkyl in THC, or Indole and Naphthalene in JWHs)
2) One hydrophobic nonbulky region (aka. the "tail" of THC or JWHs), high electronegativity group at the tail-end enhance binding.
just that, and also
3) is not required, but H-bond acceptor somewhat increase affinity (phenolic OH in THC, or keto-group in JWHs)

There are several minor points that can increase/decrease binding affinity, but I wont go into detail yet in this post unless needed.

 

[belligerent drunk]

As I said before, I'm not very familiar with CB ligands, but I do know that there are quaternary alkyl salts used as peripherally-only active drugs (opioids for example), which would suggest that the compound binds to the receptor in the charged form. If that is not the case for CB ligands, then I'm sorry.

 

[Pomzazed]

You don't have to say sorry, what you said is absolutely correct for binding of anything with 'positively charged' at physiological pH,
which is mostly from alkaloidal nitrogen position. This is true for like opioid, muscarinics, nicotinics, etc.

Cannabinoids are just some strange guys which mostly rely on hydrophobic interaction, Maybe because itself is generated from fatty part in the cell membrane itself and firing 'backward' to presynaptic receptors or so.

 

[DotChem]

^ I agree. Main interactions involving CB receptors will be hydrophobic in nature. Considering the endogenous Cannabinoid ligand Anandamide is incredibly lipophilic! It is a fatty amide (fat basically!!). So CB receptors would be expected to bind mostly lipophlic ligands like THC and the JWs.

Anandamide

BTW I wonder why the natural CB ligand Anandamide is not used directly used as cannabinoid. It looks pretty stable, easy and cheap to synthesize from arachidonic acid (ie peanut oil !

 

[sekio]

I wonder why the natural CB ligand Anandamide is not used directly used as cannabinoid. It looks pretty stable, easy and cheap to synthesize from arachidonic acid

All those double bonds mean it's not very stable compared to some other compounds, actually - they are all places for oxidation to happen, or rearrangement to a trans- double bond. And the amide on the end tends to get hydrolysed in biological environments.

Besides all that, I don't know how potent it would be... oleamide is a structurally related compound that is a CB1 agonist but I've never heard of it being used on its own as an intoxicant.