I Like to Draw Pictures of Random Molecules

[Nagelfar]

^Someone, does the above break any rules? Would it be stable at all?

Don't know why, but I've always wanted to go the *other way* with the benzoyloxy than the phenyl/simplifying route. And there are a few analogues which make a more effective compound in that direction seem viable.

 

[white55]

heh, a user on WP has a personal page that, is, perhaps meant to be a list made in the future at the following link. It has those you've mentioned above. It gives pIC50 & IC50s and CAS & PubChem #s. Nice resource.

Awesome.. am I blind or are there no numbers for flunitrazolam ?

 

[Midnight Sun]

Dresden came up with pyrrolidine subbed into mph, but I'll take credit for the idea of introducing the ring into amph

Hydrolysis into 3,4-dcmph acid would terminate all CNS effects I'm guessing, but that doesn't mean the molecule can't hit the 2b receptors in the heart which arent guarded by a BBB. Nevertheless the acid would have a short half life before it's quickly excreted I think, so I would bet that even if it did have 2b affinity, it would be short lived agonism. It's pretty interesting how a tfm group in norfenfluramine increases 2b activity several fold over amph which is pretty much negligible, as well as 5ht releasing effects. I think in terms of binding interact, once the nitrogen picks up a proton it will interact with a negative residue, but an electron rich aromatic binds weakly. Once electron density is removed from the ring, better interactions will occur (ie the electron deficient aromatic repels less) and so greater 2b affinity is the result. With that being said, could one of the chlorines in the molecule be substituted with a methoxy? The idea here is to still block the transporters, but add electron density to the ring to remove 2b affinity. It'll make the ring more prone to hydroxylation but that doesn't happen anyway, so I can't comment on the new half life. As for neurotoxicity of the o demethylated metabolite, I don't think it will enter the neuron ( I don't think ritalin does anyway, correct me if I'm wrong, maybe it just doesn't block vmat 2 and agonise taar1). I think all it's gonna do is sit on the transporter and block it, and this is going to stop say dopamine entering the 5ht cell, so I guess it's similar to how fluoxetine is hypothesised to be neuroprotective post SRA administration.

I don't think the O-demethylated metabolite would be a neurotoxic issue at all since the ester would probably be hydrolized first. I'd be interested to see what a methoxy sub would do especially considering I can't think of any stimulant, DRI or DRA, off the top of my head that used a methoxy substitution of any kind that worked, or didn't have substantial side effects (which are already a present issue in DCMP). That being said, I believe 3-chloro-methylphenidate is described in a patent somewhere and that might be a good place to start, at least to compare to DCMP itself. 3-chloro alone might do what you're talking about right? removal of one of the chlorines to return electron density to the ring (this part of your post went above my head a little, sorry ) although, if fenfluramine is any indication, 2b likes electronegative things at meta SO that idea might backfire

interestingly enough, there's an abstract out there that demonstrates vanilla methylphenidate to barely tickle 5ht receptors, including 2b.


unrelated:

 

[Nagelfar]

Similar to this "constrained "proline" analog:

Only reason I believed mine wouldn't work, was because of how close the carbmethoxy was to the phenyl

...EDIT:

 

[sekio]

Nagelfar, those sulfur containing compounds don't look feasible. Sulfur acts like oxygen or selenium; it doesn't like to go hypervalent. In fact hypervalent sulfur reagents with methylene groups act to transfer the CH2 to ketones, forming epoxides (Corey-Chayovsky reagent).

The weird disulfide-sulfinic acid thing is also a bit of a head scratcher, my gut sense is that it would fall apart in acid conditions like thiosulfate does.

It's thioethers, sulfoxides, sulfones, sulfates, or nothing. No methylenes, no sulfur atoms with hypervalent oxygens plus a free hydrogen....

Can anyone suggest why 3,4-dcmph has a long half life compared to mph?

look at logP ?

 

[aced126]

Why would it not work? The carbomethoxy is the same distance to the aromatic in mph?

Midnight, yes oxygen is electronegative and it is in the meta position, and will pull a bit of electron density via inductive effects, however the oxygen has the ability to donate a lone pair of electrons into the aromatic system (resonance effect), and I would presume this to heavily overpower the inductive withdrawing effect. Take phenol for example, the aromatic system attacks electrophiles way easier than just plain old benzene, because the oxygen lone pair is delocalised into the pi cloud.

 

[aced126]

Sorry sekio, I meant to say duration of stimulant action rather than half life. Once the carbomethoxy is hydrolysed wouldn't that kill all stimulant activity? The acid form might stay around in the body for longer but it won't cross the BBB loads?

 

[roi]

 

[clubcard]

Diclazepam was designed for a reason - duration. Anything that has x10 diazepam for ALL it's metabolites is going to be potent. Adding the triazolo reduces duration. People were sold SHITTY green diclazepam (a test batch) at first so it's reputation nose-dived. A 2mg pink diclazepam dissolved under the tongue (BID) will fix a 40mg/day diazepam habit. When the 1,4-benzos are banned - people will be buying these up ASAFP!

 

[Nagelfar]

Nagelfar, those sulfur containing compounds don't look feasible. Sulfur acts like oxygen or selenium; it doesn't like to go hypervalent. In fact hypervalent sulfur reagents with methylene groups act to transfer the CH2 to ketones, forming epoxides (Corey-Chayovsky reagent).

The weird disulfide-sulfinic acid thing is also a bit of a head scratcher, my gut sense is that it would fall apart in acid conditions like thiosulfate does.

It's thioethers, sulfoxides, sulfones, sulfates, or nothing. No methylenes, no sulfur atoms with hypervalent oxygens plus a free hydrogen....






look at logP ?

Would a nitrogen keep those sulfurs together? I'm just thinking a SH is more electronegative than a plain O, and thinking of benzoylTHIOmethylecgonine, and some of those 8 position sulfur substitutions, but using it on the 3 position bridge.

How's this, the styrene analogues on the 2B and the 3, the benzoyloxy and the carbmethoxy:

Simple enough?

 

[Dresden]

MXE is soon to be illegal here. Luckily, this one is still "legal."

1-ethylamino-1-(3-methoxyphenyl)-cyclohexane

 

[clubcard]

Look, it's as simple as 8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O

Only 1 chiral centre, no requirement for an N-O lone-pair interaction. A compound as strong & short-acting as coke BUT with that p-nitro. I don't know if it's better or worse than levamisole-laced coke but gives identical freeze and the same potency. 30mg = 50mg of UK coke so, I'm guessing, the same potency as real coke.

FREEDOM OF SPEECH

 

[sekio]

Sorry sekio, I meant to say duration of stimulant action rather than half life.

Maybe the greasy compounds just have less affinity for BuChE (butyrylcholinesterase) ?

 

[Nagelfar]

Look, it's as simple as 8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O

Only 1 chiral centre, no requirement for an N-O lone-pair interaction. A compound as strong & short-acting as coke BUT with that p-nitro. I don't know if it's better or worse than levamisole-laced coke but gives identical freeze and the same potency. 30mg = 50mg of UK coke so, I'm guessing, the same potency as real coke.

FREEDOM OF SPEECH

Gotcha, no carbmethoxy, OK.

I'm just doin' my thing though:

Checking out my "Interesting simple breakdown" thread, I noticed where it compares pethidine to a stage in the biosynthesis of morphine, and tried to take some of the steps restricting its rotation and adding them to cocaine, to get this:

 

[aced126]

Dunno how stable that peroxide would be

 

[Nagelfar]

Dunno how stable that peroxide would be

I think I could've shortened it by one, or maybe a double bond between the oxygens?

Don't know how much of a point there is to it, though forming cocaine into the closest it can get to the morphine skeleton has always been a bizarre fixation of mine. ;-p

 

[Nagelfar]

Nagelfar, those sulfur containing compounds don't look feasible. Sulfur acts like oxygen or selenium; it doesn't like to go hypervalent. In fact hypervalent sulfur reagents with methylene groups act to transfer the CH2 to ketones, forming epoxides (Corey-Chayovsky reagent).

The weird disulfide-sulfinic acid thing is also a bit of a head scratcher, my gut sense is that it would fall apart in acid conditions like thiosulfate does.

It's thioethers, sulfoxides, sulfones, sulfates, or nothing. No methylenes, no sulfur atoms with hypervalent oxygens plus a free hydrogen....

^This more feasible, sek?

 

[chatsnap]

I think I could've shortened it by one, or maybe a double bond between the oxygens?

2 oxygens with a double bond between them is O2 and won't form any more bonds

 

[clubcard]

8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O

Just input the above.

 

[Nagelfar]

8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane SMILES CN2C1CC(CC2CC1)c3ccc(cc3)N(=O)=O

Just input the above.

Gotcha.

More crab like? Remember bromo-dragon-FLY? Here's piperi-crustacean:

Hope it doesn't mean "cancer". I like it, 'cause it is the most artistic of anything I've done which may actually be functional, and as a DARI at that...


So I took the cocaine 6-alkyl-3-benzyltropanes benzyl type benzene linkage & the N-constrained phenyltropane "42a" (back-bridged tropane with extreme DA affinity) to make this beaut:

These are the kinds I just think would do wonders