Binding of DARIs

[Hammilton]

In another thread it was mentioned that there might be distinct DAT populations and that there were likely slightly different binding pockets for DARIs.

I compared a bunch of phenyltropanes to the PEA-derived DARIs and they match up pretty well. I mean, the most different I found was b-CFT compared to dimethocaine, but everything from MDPV to MPH and Dimethocaine, Cocaine, b-CFT and the RTI drugs all match up very well.

Cocaine vs. MDPV

I'm wondering what the evidence for different pockets is, because these all line up so well I don't see why that's needed to explain it.

Thanks!

(edit: oh, attachment is MPH and Dimethocaine overlayed)

 

[MurphyClox]

Could you post a 2D-picture for better comparison, please?!

 

[Hammilton]

I don't know how useful this is. In 3D you can easily see how close the amines line up but with this it's pretty impossible to see. Here's the *.c3xml file

 

[vecktor]

It is known that the amine in tropanes is not neccessary for DAT affinity yet you twist the chemdraw 3D overlay to align the nitrogens why??? you have H bond acceptors all over the place with no correlation.
one can overlay 2 small molecules in silico in any different manner of ways, not that it means anything at all.
it is pointless to regard B-CFT or any of the RTI ( Beta Beta tropanes) correlation as being significant in any way because they are essentially the same core molecule this core molecule being constrained. its like saying on overlay 4'-iodococaine and 4'chloro and 4' bromo cocaine all has absolute correlation and almost perfect overlay, of course they do because core ecogonine has not changed. I will make a further prediction based on this that paramethyl and parachloro phenyl tropane will overlay exactly, and I don't need a computer .

IIRC Mazindol and benztropine derivatives (which despite being the inverse stereochemistry at the tropane 3 position still has very high DAT affinity) are the atypical binders to WT DAT. and I tend to favour the multiple population theory with slightly different shaped binding pockets over the multiple binding site/mutiple conformer theory as a working hypothesis, it is more elegant but I don't really know, and I am not arrogant enough to presume to know.

get mazindol, benztropines and the phenyltropanes here it is worth remembering that 2beta 3alfa as well as 2beta 3beta have high DAT affinity, to overlay, then that is more interesting.

worth reading this about mutated DAT and the different effect it has on various dopamine re-uptake inhibitors.

http://jpet.aspetjournals.org/cgi/content/full/314/2/575

 

[Hammilton]

It is known that the amine in tropanes is not neccessary for DAT affinity

Interesting, I've never heard this before

Synapse. 1996 Dec;24(4):340-8.Links
Nitrogen-based drugs are not essential for blockade of monoamine transporters.Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez MD, Meltzer PC.
Department of Psychiatry, Harvard Medical School, NERPRC, Southborough, MA 01772-9102, USA. [email protected]

In brain, monoamine transporters are principal targets of widely used therapeutic drugs including antidepressants, methylphenidate (Ritalin), and the addictive drug cocaine. Without exception, these transport blocking agents contain an amine nitrogen. A prevalent view and untested premise is that an amine nitrogen is needed to bind to the same counterion on the transporter as does the amine nitrogen of the monoamine neurotransmitter. We report that several compounds without nitrogen (8-oxa-bicyclo-3-aryl-[3.2.1] octanes, or aryloxatropanes) are active at monoamine transporters. One of these, tropoxane (0-914), bound with high affinity to the dopamine (IC50: 3.35 +/- 0.39 nM), serotonin (IC50: 6.52 +/- 2.05 nM), and norepinephrine (IC50: 20.0 +/- 0.3 nM) transporters in monkey brain, the human striatal dopamine transporter (IC50: 5.01 +/- 1.74 nM), and blocked dopamine transport (IC50: 7.2 +/- 3.0 nM) in COS-7 cells transfected with the human dopamine transporter. These unique compounds require a revision of current concepts of the drug binding domains on monoamine transporters, open avenues for discovery of a new generation of drugs and raise the issue of whether mammalian transporters and receptors may respond to, as yet, undiscovered non-amine bearing neurotransmitters or drugs.

PMID: 10638825 [PubMed - indexed for MEDLINE]

it is pointless to regard B-CFT or any of the RTI ( Beta Beta tropanes) correlation as being significant in any way because they are essentially the same core molecule this core molecule being constrained. its like saying on overlay 4'-iodococaine and 4'chloro and 4' bromo cocaine all has absolute correlation and almost perfect overlay, of course they do because core ecogonine has not changed. I will make a further prediction based on this that paramethyl and parachloro phenyl tropane will overlay exactly, and I don't need a computer .

Absolutely correct. And entirely irrelevant. Just to reiterate:

phenyltropanes to the PEA-derived DARIs

 

[wungchow]

Can we get a chemical structure for tropoxane? Sounds very interesting.

 

[MurphyClox]

Can we get a chemical structure for tropoxane? Sounds very interesting.

No prob:

(1R,2S,3S,5S)-methyl 3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate

Btw, the name "tropoxane" is not official. You won't find a lot when searching for this one. Better look for "O 914".

Murphy

 

[MurphyClox]

@Hammilton: Naaaah, those amines are not really close to each other. How much nm are this? (measurement is possible in Chem3D)

I can't see any close similarity between coke and MDPV...

-Murph

 

[wungchow]

Very interesting. What's even more amazing is that replacing that oxygen with a -CH2- group retains activity as well!!

See attached text...

ref: "Textbook of Drug Design and Discovery" by Povl Krogsgaard-Larsen, Tommy Liljefors & Ulf Madsen

 

[wungchow]

Here's another article on thioether derivatives

 

[wungchow]

And an article on the plain methylene derivatives

 

[Nagelfar]

I wanted to bump this old thread.

Does anybody have any instances of the simplest molecules shown/known to act as a DARI?

 

[Epsilon Alpha]

Well to bind to DAT you pretty much just need a PEA backbone, monoamine transporters really aren't that picky. Hell I recall one MPH analog that replaced the nitrogen bearing ring with a cyclopentane ring and it still bound with about 30% of MPH's affinity

 

[Nagelfar]

Well, there's also a difference to binding to plasmalemmal DAT & VMAT, correct?

 

[Epsilon Alpha]

Found the weird one I was talking about!
http://en.wikipedia.org/wiki/O-2172

Also: http://pubs.acs.org/doi/abs/10.1021/jm040117o

 

[Nagelfar]

Found the weird one I was talking about!
http://en.wikipedia.org/wiki/O-2172

I was the one who talked Meodipt into adding that one to Wikipedia, I remember.

Also: http://pubs.acs.org/doi/abs/10.1021/jm040117o

Now *that* is interesting!

...

Lately I've been curious as to whether a drug could selectively phosphorylate VMAT2 like releasers, but only act as DARIs on plasmalemmal DAT (without phosphorylation there). I would think such would make a *very good* class of stimulant.