A question to all our metabolic pathway expects (or even those with a basic know-how)

[serotonin2A]

Butyrylcholinesterase is a non-specific enzyme which hydrolyses choline based molecules. I'm sceptical that these other molecules will be metabolised by this enzyme.

BChE is non-specific because it hydrolyzes a wide range of substrates in addition to ACh. It can metabolize drugs such a procaine, asprin, heroin, flestolol, and bambuterol.

My point anyway was that most of the molecule would be hydrolysed outside of the brain, and the little amount that is hydrolysed in the brain would likely not play a big role in the drug's mode of action unless it has a much higher binding affinity than the parent ester molecule.

If any appreciable amount of the parent drug reaches the brain then it would be succeptible to hydrolysis to 2-OH-cocaine. The assumption that most of the drug would be hydrolyzed in the periphery before it can reach the brain does not match what actually happens with drugs like cocaine, heroin, and methylphenidate. Even with cocaine, which is hydrolyzed rather rapidly, enough of the parent drug enters the brain to produce marked psychoactive effects.

Brain uptake of radiolabeled heroin in rats has been shown to be 68%. It is then deacetylated in the brain to MAM and morphine. If your assumptions were correct then heroin would never make it into the brain, and the brain would not be able to deacetylate heroin.

 

[Nagelfar]

To answer the parent question, I'd expect 2-AcO cocaine to be fairly rapidly hydrolysed to 2-OH-cocaine. Whether or not it works as a prodrug or if it sticks around remains to be seen.

Either way I'd bet it's a fun compound. Shame it would be a bastard to make, just like any of the other BzEcgonines...

Thanks sek.

I think the differing affinities of 2-AcO & 2-OH and the rapid change, onset of NET affinity specifically would make for an interesting "rush". As for benzoyl-ecgonines though, this shouldn't be one of the more difficult ones to make starting from the cocaine parent, I'd assume, probably among the most straight-forward

 

[Nagelfar]

http://www.molinspiration.com/cgi-bin/properties

Hey Aced, if you don't mind, how does one make a molecule protonated in the graph-schematic-freehand-drawing java-esque area of the above link? I put the positive charge on the nitrogen, for instance, but it won't let me put a free floating chloro with a negative charge for a HCl salt, I put the Cl on the NH, and it just overwrites it. I am trying to get the LogP for salt variants of specific drugs.

 

[aced126]

Hey Aced, if you don't mind, how does one make a molecule protonated in the graph-schematic-freehand-drawing java-esque area of the above link? I put the positive charge on the nitrogen, for instance, but it won't let me put a free floating chloro with a negative charge for a HCl salt, I put the Cl on the NH, and it just overwrites it. I am trying to get the LogP for salt variants of specific drugs.

LogP is very very low for a protonated molecule; for all practical reasons, assume that a protonated molecule cannot pass through a lipid membrane.

 

[Nagelfar]

http://www.molinspiration.com/cgi-bin/properties

The above program calculates cocaine logP as 2.62. The compound listed above is generated a logP of 2.01. A logP of 2 is optimum for crossing the BBB, lipophilic enough to cross it easily, but not too lipophilic such that it accumulates in fatty tissue etc (like benzodiazepines - very lipophilic - IV administration still has a slightly delayed onset for this reason).

Aced, how'd you get the logP of 2.01 for 2-acetyloxy-cocaine? I enter the SMILES from WP and get 2.45, what compound were you really entering, is what I want to know. I also realized that the information I entered here above is the result of a copy-error: the compound (as a prodrug) is actually more promising than I at first figured: since those values were actually for what we've figured would be its metabolite, 2-hydroxy-cocaine, which has a logP worse than cocaine's, but 2-acetoxy is still better than cocaine's regardless, and the values, though not as good as 2-hydroxy, weren't as bad as what I thought 2-hydroxy was with the copy-error, namely:

DAT: 70 ± 1, SERT: 219 ± 20, NET: 72 ± 9, LogP: 2.45

So since I err'd, and let you in on it, please let me know how you err'd. I want to know that cocaine analog that has a LogP of 2.01 ))

 

[aced126]

Aced, how'd you get the logP of 2.01 for 2-acetyloxy-cocaine? I enter the SMILES from WP and get 2.45, what compound were you really entering, is what I want to know. I also realized that the information I entered here above is the result of a copy-error: the compound (as a prodrug) is actually more promising than I at first figured: since those values were actually for what we've figured would be its metabolite, 2-hydroxy-cocaine, which has a logP worse than cocaine's, but 2-acetoxy is still better than cocaine's regardless, and the values, though not as good as 2-hydroxy, weren't as bad as what I thought 2-hydroxy was with the copy-error, namely:

DAT: 70 ± 1, SERT: 219 ± 20, NET: 72 ± 9, LogP: 2.45

So since I err'd, and let you in on it, please let me know how you err'd. I want to know that cocaine analog that has a LogP of 2.01 ))

Yes, I must've made some error as I got 2.49 when I redrew the molecule: http://www.molinspiration.com/cgi-bin/properties

The algorithm seems to be dynamic and updates itself as it receives more actual values for different compounds. For example, now it predicts a a log P of 2.93 for 2-OH-cocaine (http://www.molinspiration.com/cgi-bin/properties), which is certainly not correct (the acetylated molecule should have an increased logP). It just goes to show that predictive softwares like these have quite a big uncertainty (and the developers acknowledge this), and so these values should only be taken as rough suggestive values, not quantitative.

 

[Nagelfar]

Yes, I must've made some error as I got 2.49 when I redrew the molecule: http://www.molinspiration.com/cgi-bin/properties

The algorithm seems to be dynamic and updates itself as it receives more actual values for different compounds. For example, now it predicts a a log P of 2.93 for 2-OH-cocaine (http://www.molinspiration.com/cgi-bin/properties), which is certainly not correct (the acetylated molecule should have an increased logP). It just goes to show that predictive softwares like these have quite a big uncertainty (and the developers acknowledge this), and so these values should only be taken as rough suggestive values, not quantitative.

Well if you knew what mistake you made, even if it's faulty, some input is better than no input and ever 2.01 being a guestimate is a good starting place that I wish I knew what it was. ;-j

Also, I used the binding values for cocaine from a data set that diverges greatly from the one I originally took; it was from the same paper, but the values comparable to those compounds are:

DAT (beta-CFT )249 ± 37 SERT (paroxetine) 615 ± 120 NET (nisoxetine) 2500 ± 70 5HTT/DAT ratio 2.5 NET DAT ratio: 10.0

And those values for cocaine are *even lower potency* (e.g. higher numbers, by quite a bit at NET) so that means those compounds are *even more potent* than I originally inferred

 

[clubcard]

Marvin Sketch has cLogP & pKa values. That's your AD. As for ME, it depends on the drug in question. General answer, not intended to argue the toss over pointless detail.