I Like to Draw Pictures of Random Molecules

[N0 W4RN1NG]

Holy hell...a hexacyclo ring appeared...(holds "down + B")

 

[roi]

Just read the image name lol

http://www.sciencedirect.com/science/article/pii/S0968089613006664

https://pubchem.ncbi.nlm.nih.gov/compound/71716368

Looks like the series are sigma agonists without much monoaminergic activity at all.

 

[Nagelfar]

Has this been made? Can you post a source if so?

Of course: N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes as σ receptor ligands with potential neuroprotective effects

Looks like the series are sigma agonists without much monoaminergic activity at all.

Look again, 14b has 1.2 ± 0.1 @ DAT(!!)

 

[Pomzazed]

Wow that methylaminocubane!

You made me like it from the structure beuaty itself lol

 

[roi]

Oh yeah, but that one seems to be the only one.

(1R,2S,3S,5S,6S,7R,8R,9S,10S)-N-[(3-fluorophenyl)methyl]-N-methylpentacyclo[5.4.0.0²,⁶.0³,¹⁰.0⁵,⁹]undecan-8-amine

That is such a vastly different compound, I don't think it would be fair to call it a cocaine analogue anymore.

 

[Midnight Sun]

dirt cheap, common precursors legal everywhere. Question is whether or not the cinnamoyl ester can force a pure NMDA antagonist to fit into the MOR. my guess is probably, just with nowhere near the potency that the corresponding levorphanol base pharmacophore would have, but that's probably a good thing

 

[pr0d1gy]

Let's talk about desoxy analogs.

I've been reading into some literature that goes even further, replacing additional aryl ethers with alkyl moieties. At the end of the entry Shulgin discuss such compounds as desoxymescaline, wherein all substituents are alkyl groups. As he says these compounds are active in cats and man.

Interestingly, you can find the videos of the effects in cats at this link http://www.criticalpast.com/video/6...ecomes-inactive_2-4-6-Trimethylphenethylamine

I've recently sampled 2,4,6-trimethylphenethylamine at low dose. I won't post a trip report or anything because I don't have an HNMR yet. I can say it was certainly active and much as Shulgin described DESOXY. Also because I didn't find it very interesting or worth pursuing at higher doses.

Obviously the methyl group at the 4 position seems to be the deciding factor in making these compounds uninteresting. Any thoughts on why the 4 position is so essential in mescaline like compounds whereas alkyl substituents are active in 2,4,5-phenethylamines? Also thoughts on 2,4,6 substitutions in any form? TMA-6 is active so 2C-TMA-6 should be as well.

 

[Nagelfar]

That is such a vastly different compound, I don't think it would be fair to call it a cocaine analogue anymore.

Functional.

 

[Nagelfar]

One day, that ring is gonna be discovered to be optimized in some kinda way... I just know it...

 

[DotChem]

 

[Solipsis]

Is that pip on the left a functional substitution as is?

 

[DotChem]

phenyl isostere hopefully! .. if it is the less basic of the two Ns, it will not be charged at physiological pH! (pKa< 5??)

 

[Midnight Sun]

reminds me, the other night I had some interesting diarylethylamine ideas--

 

[adder]

If anything the N-phenethylpiperidine is the more basic one, but by a small margin anyway. Also, N-piperidinyl a biostere of phenyl? In what way?

 

[DotChem]

reminds me, the other night I had some interesting diarylethylamine ideas--

That's good idea (the top one): a dissociative opioid stim!
The (R) enantiomer may be a potent mu OP (~morphine, may be a bit less codeine?) (structure superimpose nicely on morphine!?)
and the (S) may be NMDA antagonist (superimpose on DXM) and Stim compare to (S)-PVP. Something along this line were discussed in earlier thread.(can't remember exactly):
morphinans with S stereoisomer at the C-N carbon=> NMDA antagonist
morphinans with R stereochemistry tend to give mu opioids
PS: very easy synthesis. What is the rationale for using propargyl (I mean in the second, the lefetamine analog

If anything the N-phenethylpiperidine is the more basic one, but by a small margin anyway. Also, N-piperidinyl a biostere of phenyl? In what way?

Thats why I qualify it: Hopefully!..yes it is not really classical phenyl bioisostere like cyclohexyl (see METH analog Propylhexedrine ). I figure, if the pKa of the N2 piperidinyl was low enough (< 6 ), the piperidine ring won't be charged at physiological so it might have a logP close to that of cyclohexyl. Therefore binds to the phenyl binding site with similar affinity to Ph. But of course, since it is the most basic it will be mostly protonotated at physiolocal pH so might not be the best replacement fo Ph. but if the difference of the pKa of the 2 Ns is not so large (eg 1 log unit) it might still work (10% will still be uncharged). Cyclohexyl may be better for this purpose.
The reason I thought about a piperidine there , it is way more easier to synthesize (straighforward synthesis by reacting piperidine with 1,2-dibromoethylbenzene! or substituted benzene)

 

[adder]

Does cyclohexyl really qualify as a bioisostere of phenyl? In propylhexedrine it probably only works because there's just enough space for it to act as neutral bulk, it drastically decreases potency and changes effects as well, is it even a functional DA releaser (I guess it's just an adrenergic agonist)? I thought a bioisostere is a functional group that can generally substitute for another group due to steric and electronic similarities and not a group that manages to pass as a substitute for something decreasing overall potency substantially.

 

[Solipsis]

Yeah I think it does depend, and all the variables must be checked. The phenyl you substituted in diphenidine serves too much of a different role than the phenyl in amphetamine, I believe. Probably for that reason yes ^ sounds agreeable adder.

Functional NMDA antagonists like the ACA's are modelled on NMDA and electronically mimic the carbonic acid functions of NMDA using aromatic groups loosely. While they are not exactly the heavily polar types that appear to often act as glutamate or glycine site ligands, they still carry the NMDA signature, pretty unmistakably. I personally doubt that you can just substitute the phenyl ring which is already a 'modification' into a bioisostere (i.e. broadly resembling) of a modification - that is 2 degrees removed. Could you just swap the cyclohexane in ACA's for another phenyl? Again, I doubt it since it may heavily undermine the tolerance for changes in the electronic configuration.
It seems to me that it would be so offensive to the NMDA pharmacophore that there is either a loss of potency or overall function to be expected from it.

I'm not sure if I'm right about this, mind you, but I think you can't always substitute with a cyclohexane or pip, I think you can't if the aromatic function is already a type of partial bioisostere itself.

 

[Midnight Sun]

What is the rationale for using propargyl (I mean in the second, the lefetamine analog

there really wasn't any aside from morbid curiosity: ephenidine was well-received (as far as diarylethylamines go) and I'd be curious to compare to the propargyl

that and I saw the basic skeleton lying in the morphinan structure, and was interested in approximating part of the big ol' bridge that goes from the amide to R13. I'm sure it means diddly especially permitted to freely rotate... but whatevs. lol

That's good idea (the top one): a dissociative opioid stim!

that's what methyl-ephenidine was trying to be and failed spectacularly. Unfortunately the days of the diarylethylamines are probably for the most part over now that the usual buffet of arylcyclohexylamines are now back on the market... I say unfortunately because the latter compounds all pop for PCP on drug tests and I'd rather keep my job

 

[Midnight Sun]

random methaqualone isomer... metamethaqualone?

ahh... probably yet another exercise in futility. still think the following is the best hope for quinazolinone analogues (that can actually be made at a reasonable cost)--

someday... I will expend the $ to make you a reality...

 

[Nagelfar]

These aren't mine; they're dopaminergic compounds from a patent (US 4,994,486)

I thought the "Y" and trefoil e.g. 'Isle Of Man Flag' cyclohexane inner -ring system is the most interesting since the endo-etheno bridge when it can be stabilized in the ring configuration and kept inside.