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I Like to Draw Pictures of Random Molecules

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I think one should be cautious on MPH SAR: unlike amphetamines the nitrogen of MPH piperidine is not really necessary for DA uptake inhibition: replacing the N with an oxygen atom (or even a Carbo atom to get simple cyclohexyl (like Methyl 1-cyclohexyl-phenylacetate) gives molecules that are as potent as methyl phenidate as DA uptake inhibitors!! The pharmacophores) that seem to be important are the Aryl (substitued with 1 or 2 halo is best) and the COOMe. Even the COOMe can be replaced by a simple CH2CH3 and still retain potent DA uptake inhibitors. I am not sure if that is the case with amphetamines!!

Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate https://www.ncbi.nlm.nih.gov/pubmed/12672255
imgsrv.fcgi
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This is as good as MPH (the one with a O is actually more potent!! cf ref )
 
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DotChem said:
I think one should be cautious on MPH SAR: unlike amphetamines the nitrogen of MPH piperidine is not really necessary for DA uptake inhibition: replacing the N with an oxygen atom (or even a Carbo atom to get simple cyclohexyl (like Methyl 1-cyclohexyl-phenylacetate) gives molecules that are as potent as methyl phenidate as DA uptake inhibitors!! The pharmacophores) that seem to be important are the Aryl (substitued with 1 or 2 halo is best) and the COOMe. Even the COOMe can be replaced by a simple CH2CH3 and still retain potent DA uptake inhibitors. I am not sure if that is the case with amphetamines!!

This is as good as MPH (the one with a O is actually more potent!! cf ref )
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sekio QFT; I think my point was glossed by, by some (always is), that MPH is a cousin of cocaine and not amph.
 
RandomClean3 said:
The S is sometimes used as substituted. They leave the ring alone with no double bonds since it's possible to replace with an oxygen double bond.
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Wait, are you telling me that:

FohkRz.jpg


...would work as an aromatic? ortho-oxy cocaine acts like the phenyltropane class in heightened efficacy (apart from whatever change in affinity) because the closeness of the oxygen to where the oxygen substrate site on DA is placed where the receiving loci on DAT are. Being right on the ring may be even closer with the benzoyloxy spacing; it also increases electronegativity which is shown to increase MAT ligand binding across the board.

...would this be stable?
GhqDjQ.jpg


If not then this maybe:
uk2BcY.jpg
 
sekio said:
That pyran heterocycle isn't aromatic, sadly.
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Ah, so "S" as for 'substituted in all, even unworkable, ways in this schematic of what's able to be patented for this kind' (thus RC3's insight of it's double bonds being able to be omitted in this case is useless because for the most part aromatic consistence need be maintained in that part of the pharmacophore: bit of a paradox, but so too is writing them the hexyl with circle and hexyl with double bonds for a benzene interchangeably on very same page, side by side, in one patent)
 
Hey Nags - $VENDOR is selling troparil, and I've reason to believe it's legit... thoughts? D'ya think these are going to be the Next Big Drug Problem?

Also, yeah, that markush structure looks pretty... lazy. Fo sho. Might as well just have scrapped the whole thing and written "R" on the patent for all the confusion it generates. :P
 
Offtopic but i cant resist!

LOL! Sekio, i really like the idea of the variable $VENDOR! So nice method of censoring!
What happen if we substitute the piperidine ring with a phenyl? As cyclohexyl is said to have activity
 
sekio said:
Hey Nags - $VENDOR is selling troparil, and I've reason to believe it's legit... thoughts? D'ya think these are going to be the Next Big Drug Problem?
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Not a clue. However, if it is as reinforcing as some suggest, and safer in the ways that have been assumed (non-cardiotoxic, non-neurotoxic a la amphetamine etc.) it might be a "safe" problem.

sekio said:
Also, yeah, that markush structure looks pretty... lazy. Fo sho. Might as well just have scrapped the whole thing and written "R" on the patent for all the confusion it generates. :P
Click to expand...

Yes esp. when my area of interest involves mostly these RTI patent's that F. I. Carrol et al. seem to pump out, with a like consistency, every time, for decades. ;-p As long as I notice it, I can make sure it doesn't filter it's way through to the compilation on WP I am doing of them.
 
I don't know what's going on with the library computers and snag.gy lately, but I can't screen capture the compounds I draw;

I was mixing the benztropines and the PT benztropines and getting:
(1R,2R,3S,5S)-3-[2-(diphenylmethoxy)ethoxy]-2-[3-(diphenylmethoxy)propyl]-8-methyl-8-azabicyclo[3.2.1]octane

I wonder.
 
but I can't screen capture the compounds I draw;
(1R,2R,3S,5S)-3-[2-(diphenylmethoxy)ethoxy]-2-[3-(diphenylmethoxy)propyl]-8-methyl-8-azabicyclo[3.2.1]octane
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Here; drew it for you!
(O.o looks like an squid or jellyfish or so in 2D-skeleton lol)

0T9zVb9.png
 
jpet.115.230722f1.jpg


It's the aryltropanes & benztropanes together; should have "Pirenzepine"-esque muscarinic acetylcholine receptor M1 affinity but like the above two cross the BBB perhaps.

if you check out the quinazolinamines the allosteric modulators were the longer ones, like J Pharmacol Exp Ther. 2016 Mar;356(3):624-34. doi: 10.1124/jpet.115.230722. Epub 2016 Jan 14. has for the aryltropanes and "Compound 276"
 
There is no chirality there, well I mean not in your unsubsituted structure above - here I guess there would be an ambiguous ~ line cause I can't see what X and Y are.
I guess other chirality than the axial/equatorial susbtitution of that whole moiety were not made relevant here.
 
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Not sure, man. I'd have to see some context and I didn't dive into that if it was even provided fully in a link. Maybe it is just potentially different as in not necessarily the same, but that would still be quite premature to start talking about the chirality, hey other than that you definitely have a point.

Synthesis and monoamine transporter binding of 2-(diarylmethoxymethyl)-3 beta-aryltropane derivatives. is an article that should clarify things... but I have no access
 
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Well if we say that x = flourine, y = chlorine, then the two phenyls are not equal hence the diarylmethoxy carbon is asymmetric. Do I overlook anything?

Of course if x = y, then said carbon is not chiral...
 
Do you mean if it's alpha or beta oriented? Because benztropine is levo, unlike cocaine; at the 3 ring position.

Funny fact from WP:

"...In veterinary medicine, benzatropine is used to treat priapism in stallions."
 
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