Cannabinoids with higher-order halides and alkylation

[Str]

5C-AKB-48 just recently appeared on the Swedish RC market. That's the 5-chloropentyl analog of AKB-48. Probably a potent CB1 agonist yes, but a primary halide with not much steric bulk makes me a bit worried.

What in your opinion are the chance of these to covalently bind to receptors (or anything for that matter)? Can chlorides be assumed to be safe in comparison to bromides and iodides which I feel confident would alkylate? Is there a chance that the nitrogen on the second position could facilitate in the S_N2-displacement (a la nitrogen mustard style) or are the free electrons too delocalized in the aromatic system to be nucleophilic? It would follow Baldwin's rules with 7-exo-tet which is favored.

 

[Zeds(NCO2CH2CH3)2]

Nitrogen mustards are beta halo alkyl ethyl amines, benzopyrazole is aromatic.... There will not be a Cyclization with the benzopyrazole and the chloropentyl chain...

 

[Str]

Nitrogen mustards are beta halo alkyl ethyl amines, benzopyrazole is aromatic.... There will not be a Cyclization with the benzopyrazole and the chloropentyl chain...

I figured. And you sound certain so I believe you. What are your thoughts on alkylation of cysteine or other amino acids at the active binding site?

 

[Pomzazed]

Clomethiazole has primary alkyl halide and has been used since 1930 something?

But personally I do not trust primary alkyl halide at all
(even fluoride, where it doesnt alkylate; yet goes to fluroacetate halting citric acid cycle)

 

[Str]

Clomethiazole has primary alkyl halide and has been used since 1930 something?

But personally I do not trust primary alkyl halide at all
(even fluoride, where it doesnt alkylate; yet goes to fluroacetate halting citric acid cycle)

Absolutely, there's also some sugar substitute that has a primary chloride if I remember correctly. Wasn't the fluorinated alkyl chains suspected to be the reason behind some kidney failures seen in some users? I wonder if chloroacetate would be seen as a metabolite. As I remember it though, this was only a concern on even-numbered alkyl chains.

 

[sekio]

Chloride is actually a pretty poor leaving group, all things considered. Bromides and iodides are the *really* reactive ones, and even then they usually need an appropriate nucleophile.

Anyway, just 'cause there's a primary alkyl halide doesn't make it the end of the world. (The sugar derivative you're thinking of is sucralose - a good example of how not all fluorinated or chlorinated side groups will be removed and metabolized to chloro/fluoroacetate.)

I think primary alkyl chlorides you can get away with, theyr'e just not reactive enough at biological conditions and concentrations.

 

[Zeds(NCO2CH2CH3)2]

I figured. And you sound certain so I believe you. What are your thoughts on alkylation of cysteine or other amino acids at the active binding site?

Doubtful considering these compounds bind by high entropic components (loss of water from active site) and there requires high enthalpic components or trifecta cascades in order to allow cysteine to be nucleophilic enough. Consider that alkylation will cause a total remodeling of protein structure -effectively unfolding it or distorting it, thereby the cost is incredibly high. Covalent binding of drugs happens but most notably to enzymes, albeit some receptors.. This is due to the on off time of the drug in each environment. Drugs don't bind then stop, it's a repetitive event whose rate is variable and related to its binding constant.. Enzymes and receptors are a bit different in this respect... Nitrogen mustards Alkylate the guanine bases.. For example

The problem with these cannabinoids is that they are hydrocarbon heavy and they will oxidize readily at different sites, alongside their greasy character, their residence time In the body will be longer..
Albeit that at times one oxidation is enough to make a soluble polar phase 2 conjugate(RCOOH, ROH) , these compounds have high counts of heavy atoms (non hydrogen). Thereby the classical rule of one charge per 20-30 heavy atoms accommodate solubility, in this case there is too many.. Therefore they linger and are reoxidized again.. They most likely accumulate in liver microscopes.. Or in the kidneys.. Or in the lungs (lungs contain oxidative enzymes with high surface area).. (the problem described above is common for greasy compounds and is a reason why many compounds are dropped in development).

 

[Str]

Doubtful considering these compounds bind by high entropic components (loss of water from active site) and there requires high enthalpic components or trifecta cascades in order to allow cysteine to be nucleophilic enough. Consider that alkylation will cause a total remodeling of protein structure -effectively unfolding it or distorting it, thereby the cost is incredibly high. Covalent binding of drugs happens but most notably to enzymes, albeit some receptors.. This is due to the on off time of the drug in each environment. Drugs don't bind then stop, it's a repetitive event whose rate is variable and related to its binding constant.. Enzymes and receptors are a bit different in this respect... Nitrogen mustards Alkylate the guanine bases.. For example

I'm aware of the mechanism and kinetics of ligand binding but it seems, as sekio also pointed out, I over-estimated the chloride as a leaving group. My concerns were partly based on some cytostatics and compounds like Chlornaltrexamine. But as you previously stated, these are beta chloro amines and much more electrophilic.

The problem with these cannabinoids is that they are hydrocarbon heavy and they will oxidize readily at different sites, alongside their greasy character, their residence time In the body will be longer..
Albeit that at times one oxidation is enough to make a soluble polar phase 2 conjugate(RCOOH, ROH) , these compounds have high counts of heavy atoms (non hydrogen). Thereby the classical rule of one charge per 20-30 heavy atoms accommodate solubility, in this case there is too many.. Therefore they linger and are reoxidized again.. They most likely accumulate in liver microscopes.. Or in the kidneys.. Or in the lungs (lungs contain oxidative enzymes with high surface area).. (the problem described above is common for greasy compounds and is a reason why many compounds are dropped in development).

Thank you I didn't know this. When I was taught Lipinski's rules it seemed that "fattier is better" but this makes sense.