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I Like to Draw Pictures of Random Molecules

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adder said:
First of all, 2C-X-NBOMe's doesn't seem to tolerate too many changes to their structure. DOX's drugs don't really benefit from adding NBOMe part as 2C-X's do. So you really need to be careful when you add bulk to a compound's structure.

Also, cyclohexane has completely different chemical properties from benzene. In benzene there is a lot going there, because you've got a delocalized pi system there, so its electrons are capable of creating interaction based on charges and partial charges, especially when it's also substituted. E.g. that's how dopamine interacts with DAT, its 3,4-dihydroxyphenyl part interacts with the same site as the ester part in cocaine and phenyltropanes. And that's also how, I think, the analogues of NBOMe's that I posted yesterday would substitute for LSD/LSZ and 2C-X-NBOMe's. Of course when you change one functional group to another, you have to remember that it may not have exactly the same properties even if it has the same size.

In your compound, you don't have a secondary amine there. You've got a dioxazepanone fused into the ethyl side-chain, too many oxygens there and that nitrogen won't be able to interact in the way amines in 2C-X's and 2C-X-NBOMe's interact with the 5-HT(2A) receptors. Perhaps it would be metabolised into some amount of 2C-B, but that's just about it. The 4-methylcyclohexyl part (the one that you mistook for phenyl, I guess) certainly won't substitute for 2-methoxybenzyl in NBOMe's. Generally I don't think that your original compound would be stable, also, I don't really think that it would pay off to synthesize it. But above all I think that your molecule is too big to fit in as NBOMe's fit into the receptor's cleft.
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Wow, you really know your stuff!
 
Adder, thanks for your detailed response! But I think you analyzed blueberries' compound, which I knew wouldn't work, for reasons you have described well.

I was asking about the stability of these:
os5zxu.png

wje5u1.png



Not as active compounds in their own right, but as clever pro-drugs.
 
Oh, I'm really sorry. I got set back with benzodiazepine withdrawal and I feel so dumb at times lost deep in thoughts.

With the second compound you'd probably get both 2C-B and GBL as metabolites, because these nitrogen-oxygen bonds should be fairly easy for human body to break. I'm not really sure whether you'd get appreciable amounts of these drugs, perhaps the compound or some other metabolite would be excreted very fast. But like I said, it would be a challenge to synthesize it first, you'd have a hard time finding an investor, I guess. ;) I think you need someone else more experienced to fully answer your question.

What's with the first compound? What would you really want to get as a second metabolite? Ethynol perhaps? With the triple bond there and the size of the ring your body would metabolize it into a straight chain alkenol that would be quickly hydroxylated and thus very short-lived. But that's a tricky one for me, I don't really have experience with such small molecules to be honest.
 
EDIT: @ DL- ark and black53, those are not esters actually, DL-ark yours is an ether, Black53 yours is a simple ketone(I know black, you didn't say yours WAS an ester), and both of them would have less-than-ideal conversion into 2C-B...and who knows what the parent compound would do inside the body.
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I specifically said that it's not an ester. Our law is very clear regarding this - esters and ethers of illegal substances are illegal too. So if this would metabolize to 2c-b it would be 100% legal. Now would it metabolize to 2c-b and if yes how fast/how much I have no idea.
 
Another attempt at a tapentadol based/2c ish chemical. I just read that Tapentadol is already a NARI/SRI, so this may suggest that it already acts similarly to a subsituted phenethylamine (although its self not being a substituted phenethylamine. Of course, SERT/NE affinity is not often a characteristic for psychedelic phenethylamines, however this activity may suggest that Tapentadol's structure acts similarly to phenethylamines with receptors (at the very least at NE/SERT).


The goal is a psychedelic with in vivo mu-opioid receptor agonism. 25i-Nbome has very high affinity for mu-opioid in vitro, but it is unknown whether it is an agonist/antagonist or simply has low affinity for mu-opioid in vivo.

DYpOpVZ.png


And here I have a potential new NMDA antagonist similar, but still distinctive from ketamine or MXE. Also, it kinda looks like a robot dancing! Either it is dancing or shaking it's fist at someone.

sB3GWfa.png
 
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I don't think there's a chance that your tapentadol derivative would work as an opioid. Putting chlorine on the aromatic ring likely abolishes all the opioid activity, because it's hydrophobic and there must be a group capable of forming hydrogen bonds close to the aromatic ring for an opioid to work (this applies to almost all opioids known today if not all). Perhaps you could get away with a fluoro group or a trifluoromethyl group instead of chlorine as fluorine can form hydrogen bonds, but it's not a certain thing. Fluorine can only function as a proton acceptor (but that's still rare in organic compounds) and hydroxyls can be both acceptors and donors. For a very weak mu opioid agonist like tapentadol I don't think changing hydroxyl to fluoro or trifluoromethyl would work well anyway.

The ortho-methoxy group in your compound corresponds to C4 in morphinan and there are quite a few morphinans that have hydroxy or methoxy there instead of substitution at C3, so after demethylation the hydroxyl there might work if it wasn't for the chloro (and probably the other methoxy) that would mask it.

What's up with the additional primary amine at beta-carbon in the alkyl chain? This is what could kill both opioid and serotonergic activity. Without that amine, the N-demethylated and N,N-dimethylated metabolites could be SRIs.

The other compound doesn't really follow any SAR for dissociatives, at best it could interact with SERT (and perhaps NAT).
 
adder said:
I don't think there's a chance that your tapentadol derivative would work as an opioid. Putting chlorine on the aromatic ring likely abolishes all the opioid activity, because it's hydrophobic and there must be a group capable of forming hydrogen bonds close to the aromatic ring for an opioid to work (this applies to almost all opioids known today if not all). Perhaps you could get away with a fluoro group or a trifluoromethyl group instead of chlorine as fluorine can form hydrogen bonds, but it's not a certain thing. Fluorine can only function as a proton acceptor (but that's still rare in organic compounds) and hydroxyls can be both acceptors and donors. For a very weak mu opioid agonist like tapentadol I don't think changing hydroxyl to fluoro or trifluoromethyl would work well anyway.

The ortho-methoxy group in your compound corresponds to C4 in morphinan and there are quite a few morphinans that have hydroxy or methoxy there instead of substitution at C3, so after demethylation the hydroxyl there might work if it wasn't for the chloro (and probably the other methoxy) that would mask it.

What's up with the additional primary amine at beta-carbon in the alkyl chain? This is what could kill both opioid and serotonergic activity. Without that amine, the N-demethylated and N,N-dimethylated metabolites could be SRIs.

The other compound doesn't really follow any SAR for dissociatives, at best it could interact with SERT (and perhaps NAT).
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Eh, the amine is to make it more phenethylaminy, I put it in there and meant to remove it but forgot when I actually generated the image to do that.

What if it was the S- S- entiamer of tapentadol, which is more potent on mu-opioid, would that work better with a chlorine? Or better yet, what if I replaced the chlorine with an ethyl?
 
Tapentadol mostly relies on its spatial configuration to fit into mu opioid receptors, so changing stereochemistry would be a bad idea.

If you replaced chlorine with an ethyl, that wouldn't do anything good for opioid activity. Ethyl (generally alkyl) and chloro are both hydrophobic groups, and you need a hydrophilic group on the aromatic ring. Classes of compounds capable of hydrophilic interaction are alcohols, carboxylic acids, amines, amides, also sulfonic acids, sulfonamides, etc. etc. Using a methoxy instead, perhaps you could end up with some psychedelic compound a la TMAs that could be metabolised into an active opioid. But honestly I think it's going to be much harder than that. The SARs for opioids and psychedelics differ so much that I guess you will need to work in 3D to design a compound that could be both an opioid and a 5-HT(2A) receptor agonist psychedelic. Additional methoxy groups as in phenethylamines may be too much to fit into MOP receptors. Just look at how complex ibogaine and its analogues are to bind at both 5-HT(2A) and opioid receptors and it only does it effectively at relatively high doses.

Of course depending on the rest of a compound's molecule you don't necessarily need a phenolic hydroxy group to have an opioid. Pethidine and methadone don't have a hydroxy on their aromatic rings and yet they're both quite potent compared with morphine. There's a nice article on the 3D model of a pharmacophore for mu opioid receptors. It also compares how various opioids overlap. It's called "Consensus 3D Model of μ-Opioid Receptor Ligand Efficacy based on a Quantitative Conformationally Sampled Pharmacophore". Also, try googling for an image showing beta-FNA binding to a mu opioid receptor, it gives a general idea where and what types of functional groups you need in a compound to make it an opioid, it should be somewhere on www.nature.com. I think it's a good start. Then you can look for some sites and articles on bioisosterism, it's used to design new compounds based on existing ones.

This is such a complex subject that a small message on a board isn't enough to fit in all the important stuff about it. At the beginning almost every time I searched for some little bit of information when something was wrong with my idea, there was a lot of things new to me and I'm still learning the ropes.:D
 
and even if you did come up with a compound that bound to both the mu opioid receptor and the 5ht-2a receptor, there's no telling whether the relative potency of the two effects would be balanced enough for the chemical to effectively fill both functions at doses that are both noticeable and safe. if its potency as an opioid is 10x higher than its potency as a psychedelic then you would pass out or die before you started to trip. conversely, if its potency as a psychedelic was 10x higher than its potency as an opioid then your ego would be pretty much shattered before you even felt so much as a numb opioid itch.
 
thenightwatch said:
and even if you did come up with a compound that bound to both the mu opioid receptor and the 5ht-2a receptor, there's no telling whether the relative potency of the two effects would be balanced enough for the chemical to effectively fill both functions at doses that are both noticeable and safe. if its potency as an opioid is 10x higher than its potency as a psychedelic then you would pass out or die before you started to trip. conversely, if its potency as a psychedelic was 10x higher than its potency as an opioid then your ego would be pretty much shattered before you even felt so much as a numb opioid itch.
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Thats why it is a challenge!

anyway @adder thanks for the suggestions on where to look for info, definitely going to check those out at some point.
 
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They don't have names. The increased rigidity of the fourth one should increase potency compared to 2C-X fly but I don't believe that's ever been made, perhaps due to synthesis challenges.
 
It was meant more as what would you call them if they were made or what would be a logical name for them.

I'd call the first DOC-fly and the second 2c-c-saturatedfly.
 
black53 said:
It was meant more as what would you call them if they were made or what would be a logical name for them.

I'd call the first DOC-fly and the second 2c-c-saturatedfly.
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That would be 2c-c-unsaturatedfly; bit of a mouthful.
 
Yeah, I'm retarded today. Not only the saturated/unsaturated mistake, but I called DOC-fly DOB-fly on another board :)

2c-c-fruitfly? (since fly, dragonfly and butterfly are already taken)
 
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