I Like to Draw Pictures of Random Molecules

[Nagelfar]

What exactly makes a compound selective dopamine reuptake/releaser or selective serotonin-dopamine reuptake/releaser devoid of any norepinephrine activity? It is extremelly difficult to separate DAT and NET activity as the two transporters have virtually identical susbsttrate requirements. More difficult still is separating NET from DAT activities while retaning SERT activity intact. They are only 2 known compounds that are selective SDRI.

As about the SDRIs and phenyltropanes, check out this paper by Kuhar et al. and you'll see that there are many better SDRIs without NET affinity than RTI-83. (e.g. Those are not the "only two", far from it) This paper, unlike Singh's (pg. 9), says that RTI-304 is not infact 28,000 for displacement of NET but only 2,799. (which would make it not the, by far & wide, most selective SDRI known. *However* I've noted several typographical errors, esp. in the 2D structure of the PT compounds given; i.e. RTI-111 and RTI-112 are both given as di-chloro with just different conjugate salts, when in-fact the latter is para-chloro, meta-methyl according to other sources. And RTI compounds don't seem to have given any shorthand specific names to variants due only to salt form alone.

 

[roi]

3'-HO-2'-HO-Ephenidine - I think it would be a bit opioid-ish.

I also have a good feeling about

 

[abaddamn]

Furanylpsilocin

Looks like a triptan.



Here are a few coke variants. The first one seems a bit silly and may not even work lol.

Ethyl ester of Salycycl ecgonine. Methyl ester said to be 10x stronger than coke.

Ethyl ester of 4-fluro cocaine.

 

[DotChem]

As about the SDRIs and phenyltropanes, check out this paper by Kuhar et al. and you'll see that there are many better SDRIs without NET affinity than RTI-83. (e.g. Those are not the "only two", far from it) This paper, unlike Singh's (pg. 9), says that RTI-304 is not infact 28,000 for displacement of NET but only 2,799. (which would make it not the, by far & wide, most selective SDRI known. *However* I've noted several typographical errors, esp. in the 2D structure of the PT compounds given; i.e. RTI-111 and RTI-112 are both given as di-chloro with just different conjugate salts, when in-fact the latter is para-chloro, meta-methyl according to other sources. And RTI compounds don't seem to have given any shorthand specific names to variants due only to salt form alone.

@nag:right. there are lots of tropanes with some selectivity for DAT SERT and no NET. I lump them all together in saying only 2 compounds . should've said: 2 "class" of compounds: the aryl trapanes and the UWAs. Now, imho the absolute Ki values matter less than the relative values. These are the ones that gives a better idea of the binding profile of a given compound and its psychoactivity. The relative values as defined by a selectivity index (ie Ki(DAT)/Ki(SERT) or Ki(DAT/NET)....etc) is what matters most IMHO. So a binding constant of UWA-101 of 28000nM or 4000nM is not really the point. 4000uM gives a SI(DAT/NET) of ~ 50xtimes. Pretty huge. The interesting thing is that is very rare("all" DAT inhibitors also inhibit NET ..the opposite is not true.) The chllenge is how to get selective DAT/SERT inhibitors ie with a selectivity index as high as possible. yea, thse are not the only compounds. I shouldve said class aryltropanes and Methylenedioxymethamphetamine anlogs.

For ex cocaine is a pretty shitty reuptake inhibitor(Ki for DAT SERT and NET in uM range.. pretty high!). But it binds and inhibits the reuptake of all 3 NTs with similar potency which gives it its unique profile and the psychoactivity it has; albeit all things being equal (PK MOA...etc). The question is how do you design Selective Dopamine Serotonin Reuptake Inhibitor? Selective DRIs are relatively abundant (eg amfonelic acid or 3C-PEP piperazine) not so for SDRIs

I am medicinal chemist drug designer by training so my interest in asking that question is really about a compound structural features that makes it a SDRI or NDRI or selective DRI for that matter!

 

[Nagelfar]

@nag:right. there are lots of tropanes with some selectivity for DAT SERT and no NET. I lump them all together in saying only 2 compounds . should've said: 2 "class" of compounds: the aryl trapanes and the UWAs.

I noticed another source giving the smaller spread for RTI-304, though it's another RTI patent: it is Singh's paper (possibly it alone?) that gives the extremely high NET/DAT ratio of 1,867× for RTI-304

Other RTI patents (on google) for instance similarly give "2,799" and not "28,000". So perhaps this was a singular error with Singh's publishing, either that, or a pervasive RTI copy-error.

Other sources lump ones like RTI-298 as SDRIs and it's NET/DAT is only 93× (and SERT affinity is ten times lower than DAT even, so part way in-between), so I suppose as you say the ~50× against NET with DAT and moderate low numbers for SERT makes one a relative SDRI.

 

[pr0d1gy]

I found a publication regarding 5-thienyl and 5-furanyl analogs of benzos. Interestingly some of these analogs are active. 5(2')-thienyls and 5(3')-furanyls both had IC50s low enough to be considered active. They were also found to have anticonvulsant effects. I'm in the process of acquiring the 5(2')-thienyl analog of diazepam. Its IC50 is reported to be about equal to bromazepam. Another cool note, in the case of these compounds alkylation of the free amine didn't seem to make a huge difference. As expected n-methyl was more potent, but less so than the case of diazepam/nordiazepam.

Any comments on the implications of these compounds?

 

[DotChem]

I noticed another source giving the smaller spread for RTI-304, though it's another RTI patent: it is Singh's paper (possibly it alone?) that gives the extremely high NET/DAT ratio of 1,867× for RTI-304

Other RTI patents (on google) for instance similarly give "2,799" and not "28,000". So perhaps this was a singular error with Singh's publishing, either that, or a pervasive RTI copy-error.

You're right. It might be a typo. The IC50 of RT-304 reported by Singh is too high The one reported in the patent you cited and in this paper here is the correct value. Keep in mind though Singh's paper is just a review paper with "thousands" of Ki IC50 and EC50s of hundred of compounds. So an error is bound to slip up once in while. The most reliable is the one reported in the reference Singh cited . The correct value should be 2,800nM (2,799..) instead of 28,000nM. Maybe you should edit the wiki entry when you have time.

 

[MDMQ]

1P-ETH-LAZ

3-HO-TCE

BOTFM-DragonFLY

 

[Midnight Sun]

Would acetylating both terminal hydroxyls on GHB help or hurt its already shit poor BA%?

 

[psychonauticus]

New substance structures

Hello everybody! A friend of mine, draw a few structures for possible new substances. What do you think, do they have any sense?
Thanks for any feedback.

 

[roi]

See the random structure thread in the stickied post section.

 

[psychonauticus]

Oh, thanks. I didn't see it.
Could I please mr. moderator, to move it this http://www.bluelight.org/vb/threads/582708-I-like-to-draw-pictures-of-random-molecules thread? Thank you

 

[roi]

TNTA

 

[Dresden]

I've thought of that one before except that I let the carbon in the amine side chain count as its methyl group.

 

[Dresden]

 

[Dresden]

Note the similarity.

 

[Dresden]

See also.

 

[Nagelfar]

RTI-143 (NET/DAT selectivity ratio of 9,919, over nine-thouuuuusand!) @ 2-beta substitution + RTI-436 (634.6 NET/DAT ratio) @ 3-beta para-benzene position.

Furthermore, if you compare RTI-195 to RTI-199 (pg. 16, bottom two), where the only difference is a sulfur on the latter to the oxygen on the shared heterocycle at the C2 pos., it changes NET value from 1,310 to 24,320.8 (however, the substitution pattern in the heterocycle is different than in RTI-143, and since electrostatic factors contribute in the case of C2, I'm adding rather than omitting, but without making a heterocylic di-aryl (which one would think to have had an example somewhere in literature that someone studying this nigh a decade as I have would have come across but have not so figure it'd gimp the structure completely) and keeping the electrostatic sub-pattern the same have added an internal-to-cyclopentane diaziridine to the nitrogens; meaning also putting in a near chlorine sub. on the aryl like in RTI-143 also as the di-subs show little difference between the para and meta when it comes to halogens with PTs @ the C3, so I added the C3 chlorine without forgoing the 436's para-(trans)stilbene skeleton. So taking that into account:

(though looking at its least energy state, it's more of some trilactam than a diaziridine... trilactam, sounds very "Revenge Of The Nerds-ish")

Also an extreme extended length para-pos., rigid triple bond terminating in a second phenyl on the PT C3 phenyl (namesake 'phenyl' phenyl with a side-chain phenyl attached thereon) has much higher binding than expected when longer substitutions have otherwise impaired binding from there, making it be postulated that there is another remote binding domain on DAT far off from the 180 degree nominally usual ending of the inherent PT phenyl's binding range

i.e.

third best = 3.7 @ DAT binding⤴

2nd Best = 3.09 @ DAT binding⤴

BEST = 1.82 @ DAT binding⤴

fourth best, or "worst of the triple-phenyl-terminating" = 6.28 @ DAT binding (still good! compared to..)⤴

Whereas for example:

tamagnan is half as potent as the worst above w/ a value of 12 @ DAT⤴

and

isopropyl-para-PT is a shockingly low 597 (five-hundred-ninety-seven) @ DAT ligand affinity(!)⤴


So following this rationale, is there anybody who has access to a 3D rendering program who could tell which of the triple-phenyl-ending-para substitutions (specifically the best / second longest one third down from top) best overlays with a 2-naphthyl substituted PT (or "NT" as it were, i.e. naphthyltropane, just perhaps?) with what would be a similar, equivalent (in 3D) addition but instead on its 6, 7 or 8 position (since it's a naphthyl there's a lot more than the phenyl, of course)?

For instance:

...could someone come up with something potentially better than the above using the naphthyl idea? (since the PT naphthyl alone, without making use of the putative "extra" binding domain on DAT off along in space beyond the phenyl, has a DAT affinity of 0.51, a SERT of 0.80, and a NET of 21.1, such might be very promising if such another binding domain is being used)

 

[Nagelfar]

 

[roi]

clenbuterol inspired