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I Like to Draw Pictures of Random Molecules

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GHB derivatives:

ghb-der.png


Note that even though there's three carbon atoms between the hydroxy and carboxyl groups in all of the molecules, the actual spatial distance between them depends on bond angles(size of the ring). What's the optimal distance for receptor binding?
 
Here's a list of GHB derivatives and the corresponding distances from alcohol oxygen to carbonyl carbon in the energy minimized structure. I think the cyclohexanemethanol carboxylic acid has the groups too close together.
trans 3-OH C7 acid 4.968
GHB 4.935
trans 3-OH C6 acid 4.921
S-4-Me-GHB (S-GHV) 4.914
GHV 4.912
cis 3-OH C7 acid 4.824
t-HCA 4.719
cis 3-OH C5 acid 4.694
cis 3-OH C6 acid 4.409
trans 3-OH C5 acid 4.395
S-3-Me-GHB 4.382
S-2-Me-GHB 4.331
R-2-Me-GHB 4.328
R-4-Me-GHB (R-GHV) 4.314
R-3-Me-GHB 4.305
Click to expand...
 
fent-tryp.png


When thinking about rings of different sizes, I imagined the ring-expanded fentanyl derivative above... Unfortunately when I did a google search with keywords 'fentanyl' and 'ring expansion', I found out that someone has already made that compound and that it's less potent than fentanyl itself. (but there's lots of new positions to put substituents in)

In TIHKAL, Shulgin writes about N,N-dialkyl substituted tryptamines... Why can't the nitrogen atom be part of a ring, like in the second picture?

EDIT: Maybe expand the piperazine ring in BZP to a seven-atom ring, I don't think anyone has tried that...
 
Shulgin touches on the piperidine analog of the tryptamine - pip-T - and it seems to be a very strange and malicious compound indeed.
 
I often invent 'new' compounds and then find out that someones already made them...

I looked for info about the ring-expanded BZP derivative (N-benzyl homopiperazine), and some chemical company seems to be supplying it. A similar derivative has been made from the antihistamine chlorcyclizine and it seems to retain H1 antagonist activity while also binding to DA and 5HT receptors. Would that ring-expanded BZP be considered a controlled substance analog in USA?
 
bzethyl.png


I find the compounds of N-benzyl ethylenediamine class interesting. It might first seem that there's no a priori reason to expect them to act as DRIs, but note that they are essentially open-chain versions of benzylpiperazine, without the second ethylene bridge connecting the nitrogens.

The antihistamine tripelennamine(lower picture) has this structure, and it's known to be a weak dopamine reuptake inhibitor... Maybe there's some compound of this class that would have enough DRI potency to be used as an amphetamine-like stimulant.
 
Sorry if this is too newbie-ish, but is it generally understood what makes a drug more or less potent? Why is 4-FA so much weaker than d-AMP or d-methamphetamine? It ought to be roughly as lipophilic as d-AMP, and generally share most chemical characteristics with d-AMP (except the fluorine probably makes the aromatic ring more polar). Would it be that you need a higher concentration in the brain, due to weaker receptor binding? A couple of papers I found put the EC50s for NE release at 7.2e-9 and 3.7e-8 for d-AMP and 4-FA, respectively, in molar, about a 5x difference in favor of d-AMP (rat brain in vitro). For DA it's 8.0e-9 and 2.0e-7, respectively, a 25x difference in favor of d-AMP. Does this account for the whole difference? It seems like there is no amount of 4-FA that will get you as messed up as d-AMP. Is there any way to predict this or account for it based on the structure?
 
4-FA is also a serotonin releaser whereas D-amp is not. It's also worthwhile to note that 4-FA cannot be metabolized via p-hydroxylation unlike D-amp.

The 25x preference for DAT for D-amp over 4-FA is the major issue. Lower EC50s at the transporters = more effective as a monoamine releaser = generally more abusable, euphoric, and toxic.
 
sekio said:
4-FA is also a serotonin releaser whereas D-amp is not. It's also worthwhile to note that 4-FA cannot be metabolized via p-hydroxylation unlike D-amp.
Click to expand...
Your point about 5-HT is well taken, but 4-FA ought to cause subjective effects even if it's just releasing 5-HT, shouldn't it? I mean, 5-HT release may antagonize the DAergic effects, but it shouldn't necessarily decrease the overall subjective feeling of being high, right? Unless 5-HT release itself causes little or no subjective effects, while still diminishing the DAergic effects. That would help explain why drugs like MDAI are said to not feel like much by themselves.

Wouldn't that difference in metabolism tend to increase the potency of 4-FA relative to d-AMP?

The 25x preference for DAT for D-amp over 4-FA is the major issue. Lower EC50s at the transporters = more effective as a monoamine releaser = generally more abusable, euphoric, and toxic.
Click to expand...
Does that place a ceiling on the effect of a drug like 4-FA, or can you compensate with higher doses?
 
3benzoyloxyethyltropane6acetylmorphine.jpg


I wonder how effective this would be and how it would metabolize.

This one might be a bit more predictable:

36cocainemorphine.jpg


^I wonder how many millions of times this one has been drawn by chemistry student drug enthusiasts?
 
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