I Like to Draw Pictures of Random Molecules

[aced126]

Also I think for synthesis discussion, saying "reduction from x to y" etc should be allowed given that absolutely no reagents or practical details are given. Especially if doing so can open up on new insights relating to pharmacodynamic and pharmacokinetic properties of said compound.

 

[Solipsis]

I like that... no synthesis but magical transformations rules on alchemy?? : p

 

[Nagelfar]

The chromium tricarbonyl compounds should act as a carbon monoxide-releasing agent. They release CO to myoglobin.

Edit: Something like [{(MeO)2C6H4}Cr(CO)3]. See page 267.

"...on photolysis..." I don't think there's much room for light to get into an intravenous preparation. ;-P or am I showing my ignorance dramatically? ;p

i'm gonna say that an organic-soluble Cr(0) source is probably a great way to fuck up enzymes non-specifically by delivering heavy metal ions to all sorts of places they normally would never make it.... so toxic like lead, uranium, thallium, polonium type stuff. heavily bioaccumulative i'd bet. methamphetamine's monoamine release/pro-oxidative effects are tame in comparison.

look at the toxicity of nickel carbonyl for a scare... and also for why nobody uses metal carbonyls as drugs.

Well, I think of the man who ate colloidal silver as a daily supplement for years straight, but all it did to him was turn him into a smurf (or hindu God?)

 

[Friman1987]

Now as for the molecule I drew notice it is actually not chiral (it is symmetrical!) so can well equally bind LSD receptors (2a/2c) opioids (compare to morphinans) and NMDA (compare to lefetamine) in addition to potentially beeing DRI DRA .. PRETTY NASTY I GUESS

This one should works as you say, DRI,NRI and mybe like amphetamine have some kind of monoamine releasing property.

Would be surprised if it wasn't described somewhere in literature!!). But then again naphthalenes tend to be carciogenic, isnt it?

Why not making it more polar?

some of these should be active. I dont no which one. You can do 1000 other structures with this one, you might come up with something better.

 

[roi]

 

[DotChem]

Tramadol losing potency as the alkyl chain between N and phenyl group increases is not surprising. Tramadol and other open chain opioids are more likely to conform in a slightly different and more accessible way than classical opiates to the receptor. Adding the N-phenalkyl group will not mean that it is likely to interact with the hydrophobic pocket as it would be with classical opioids. Steric hindrance is more likely the case here, and this should be the case especially if activity drops as n increases (I haven't read the paper yet).

You're right. Like I said someone on this thread sometime ago (cant remember) suggested phenethyl tramadol. The rational beeing that replacing the N-methyl of morphine or meperidine with a phenethyl increase potency by at least 10times. So theoretically it should be at lest 10x tramadol at mu. The authors of that paper use similar reasoning. But apparently it doesnt work (no more active than the N-methyl).

 

[DotChem]

This one should works as you say, DRI,NRI and mybe like amphetamine have some kind of monoamine releasing property.

Why not making it more polar?

some of these should be active. I dont no which one. You can do 1000 other structures with this one, you might come up with something better.

Why would you want make'em more polar? cLogP of 2.37 seems pretty excellent to me as far as BBB transport is concerned + shorter distribution T1/2 giving fast acting drug molecule because of less non-specific protein binding!

 

[DotChem]

@Friman1987

Oh I see: so the indole NH is required for LSD binding (as agonist!!!?) to 2a. Hydrogen bond to Ser 546? But usually H-bond gain of affinity is not that huge (10x times at best!) and since LSD is EXTREMELY POTENT 5HT2a agonist, one can live with that I guess. Problem is if that (not having H-bond donor there) will still result in agonist rather than antagonist!

So may be this?

ie

extremely easy synthesis but CAUTION the opposite stereochemistry at the C-N might well results in a potent opioid so a racemic mixture might well give psychedelic opiates. But that's all theoretical until someone make and test it!!!

 

[aced126]

I like that... no synthesis but magical transformations rules on alchemy?? : p

Not necessarily a "magical transformation" lol, but a transformation which is known to be possible, but nothing is revealed practically in achieving that.

 

[aced126]

It would be interesting to see how the thiophene moiety substitutes for the methyl in compounds 2 and 5.

I thought of and posted guanidine amphetamine a while ago here. It could work. Provided it's a fair substrate at DAT and can agonise TAAR1 effectively, it is likely to increase cytosolic [DA] loads due to increased basicity over amphetamine, and thus increase synaptic [DA]. There might be pharmacokinetic problems however.

 

[aced126]

.

.

Really enjoying the rational drug design from both of you, keep it up

Open chain lysergic acid analogues seem like a great idea

 

[aced126]

Have benzodiazepine derivates with isosteres for the heteroatoms been synthesized?

https://en.wikipedia.org/wiki/Medazepam
http://www.benzo.org.uk/bzequiv.htm

Medazepam is diazepam without the carbonyl oxygen; it is of equivalent potency according to the table above. It'd be more lipophilic so one could assume increased lipophilicity compensates for reduced binding interactions, but the 2 molecules as a whole are so lipophilic anyway I don't think it matters. Anyway if the carbonyl oxygen is not crucial to activity, what says other heteroatoms are?

If anyone knows of a SAR study considering these ideas, a link would be much appreciated.

Diazepam:

Proposed derivatives:

One like the above but nitrogen in 4 position instead of 1, 1 position replaced by a carbon (Opsin not rendering it correctly).

 

[Solipsis]

The oxygen and nitrogen are involved in hydrogen bond accepting sites of the benzo binding site..
But no they are not the most important for receptor affinity... that would be the 7 and 2' position.

As long as you keep the 4-5 double bond it should be fit for hydrogen bond accepting... but your omittance of the oxygen might not be so affordable because it doesn't allow a hydrogen bond. So get some electronegative shizzle going over there, not a methyl..

http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.1999.tb00094.x/pdf

 

[aced126]

The oxygen and nitrogen are involved in hydrogen bond accepting sites of the benzo binding site..
But no they are not the most important for receptor affinity... that would be the 7 and 2' position.

As long as you keep the 4-5 double bond it should be fit for hydrogen bond accepting... but your omittance of the oxygen might not be so affordable because it doesn't allow a hydrogen bond. So get some electronegative shizzle going over there, not a methyl..

http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.1999.tb00094.x/pdf

Cheers, I'll look into that.

 

[Friman1987]

Why would you want make'em more polar? cLogP of 2.37 seems pretty excellent to me as far as BBB transport is concerned + shorter distribution T1/2 giving fast acting drug molecule because of less non-specific protein binding!

- Naphthalene is carcinogenic because of the formation of epoxide metabolism.
- Naphthylamine is also carcinogenic, gives bladder carcinogenesis.

http://pharmrev.aspetjournals.org/content/49/4/403.full

The amino-group is directly attached to an aromatic ring and that makes it impossible to metabolize away the amino group from the naphthylamine. That complicates the metabolism.
But that structure that you gave have not the same kind of issue as naphthalene amine. I wonder if it will act as an MAO inhibitor like many other alpha-substituted amphetamine? I guess that this molecule should be difficult to metabolize.
We do not know how toxic it is, making it more polar makes you care less about toxicity.
If you have para Chloroamphetamine which have neurotoxic property and then you add beta-keton to it, then you will get 4Cl-cathinone which do not have same toxicity or mechanism of action as p-Chloroamphetamine.

 

[roi]

UWA-001 and Ephenidine hybrid. Possible psychedelic, stimulant and dissociative in one molecule?

 

[Friman1987]

 

[DotChem]

Have benzodiazepine derivates with isosteres for the heteroatoms been synthesized?

https://en.wikipedia.org/wiki/Medazepam
http://www.benzo.org.uk/bzequiv.htm

Medazepam is diazepam without the carbonyl oxygen; it is of equivalent potency according to the table above. It'd be more lipophilic so one could assume increased lipophilicity compensates for reduced binding interactions, but the 2 molecules as a whole are so lipophilic anyway I don't think it matters. Anyway if the carbonyl oxygen is not crucial to activity, what says other heteroatoms are?

If anyone knows of a SAR study considering these ideas, a link would be much appreciated.

Diazepam:

Proposed derivatives:

One like the above but nitrogen in 4 position instead of 1, 1 position replaced by a carbon (Opsin not rendering it correctly).

I guess it should work in principles as long as the crucial 7-Cl is there! conformation is similar to diazepam. For the first one but with the carbonyl (similar molecule described here

just add chlorine at 7 (and 2') but then it gets way too lipoliphilic which may be a good thing for benzos since it might give them longer duration(depot in fat tissues and released slowly). but how crucial the C=N is besides making diazepam more polar than the C=C analog???

and diazepam

I like the last molecule

 

[DotChem]

I mean this one:

It is actually known molecule described here and in some old patents in the 80s

 

[DotChem]

@Friman184
Naphthalene is carcinogenic because of the formation of epoxide metabolism.
Naphthylamine is also carcinogenic, gives bladder carcinogenesis.

That's right. they tend to give electrophilic epoxides metabolites leading to DNA damage among other is big issue which I was mentioned earlier. But notice that not all naphthalenes are carcinogenic: the common antiinflammatory Naproxen (AleveTM) is pretty safe drug!

@Friman187 But that structure that you gave have not the same kind of issue as naphthalene amine. I wonder if it will act as an MAO inhibitor like many other alpha-substituted amphetamine? I guess that this molecule should be difficult to metabolize.
We do not know how toxic it is, making it more polar makes you care less about toxicity

True it is not really an aromatic amines which might give rise to toxic nitroso metabolites..
and yes it might be pretty resistant to MAO metabolism (may or not be MAO inhibitor!) hard to tell but my guess it would probably be close to Bromo-dragonFLY in terms of ADMET but definetely different from simple amphetamines.

wiki BromoDragonFLY It has a much longer duration of action than LSD and can last for up to 2–3 days^[3] following a single large dose, with a slow onset of action that can take up to 6 hours before the effects are felt.