Structural Requirements for Zolpidem-Thalidomide Depressants

[Ham-milton]

I've been doing a lot of research into a Pan-Depressant SAR, and right now I've been working on a-keto-T derivatives.

AMT (Imagine the alpha-methyl is a ketone)

Zolpidem

Zopiclone

SX-3228 (missing the benzene, and has a double bond in that chain, but it's still a1 selective)

Thalidomide

It's a pretty common structural element, so I was wondering if there had been any papers written on the SARs of these sorts of drugs. I'm having a hard time finding anything. Not sure if I'm searching wrong or just really innovative. I doubt I'm the first to see this.

 

[leungkachong]

Well, I'd be extremely surprised if there was any pharmacological similarity in receptor binding as a result of this. It would definitely have an effect on the interaction w/ the binding domain (formation of salt-bridge) with whatever receptor it is interacting with... but not actually in the actual receptors involved.

If you wanna look pan-'depressant', look at the relative receptor populations in the regions of the brain which are important to the effects you are talking about. You actually might want to look at stuff which works on imidazoline (which is actually the newly theorized method of action for clonidine even).

 

[Ham-milton]

These are all α1 selective, with the possible exception of thalidomide, which I can't find information on it's particular binding properties.

 

[UnfortunateSquid]

What's a common structural element? I see no structural similarities between those 5 drugs...

 

[Ham-milton]

Really? Okay, I'll draw it:

It doesn't seem to matter a whole lot what sort of pentagonal ring is used, but they all contain at least one nitrogen. Not sure if that's necessary or not.

In 90% of GABAergic depressants, you'll find NC(=O)C, NC(=O)O or NC(=O)N in it. This makes sense- that's essentially a GABA mimic. It seems that replacing the OH with an NH makes the structure more potent (think Valpromide vs. Valproic Acid).

 

[Riemann Zeta]

I think that might stretching what can be called a 'significant structural commonality' a little. You are right about amides (be them right out in the open a la meprobamate or hidden like a benzo) in GABA-A modulators, but (1) the valpro- compounds are not GABAergic and (2) the 'z' drugs are pretty heterogeneous pharmacologically, despite their similar effect.

 

[Ham-milton]

(1) the valpro- compounds are not GABAergic and (2) the 'z' drugs are pretty heterogeneous pharmacologically, despite their similar effect.

1. I wasn't saying they were, but rather that as GABA-mimics, having an NH beats out an OH in potency. Ion Channel-drugs also (most of the time) retain these same features.

2. I don't think so. In GABA-A a1-selective drugs, this feature is ubiquitous. Z-drugs in general aren't what I'm talking about. I'm talking about those drugs that contain this feature. They're a1 specific.

Zaleplon, which doesn't contain this feature- but does still retain the "gaba-mimicing element" which is presumably a very important feature for GABA-A receptor binding. If Zaleplon were modified with this Pentagon-C-C(=O)-N, it seems like a fair bet that it'd be a1 specific.

As it is, it's ω1-specific.

I also belief that, Zolpidem, the serotonergic-style visuals seen under its influence are a result of it being so similar to DMT. Zopiclone, which still contains this substructure, is less likely than Zolpidem, but more likely than the other depressants to cause visual disturbances. If Thalidomide were missing the rest of the piperidyl ring, I would imagine it'd also produce visuals.

I think that might stretching what can be called a 'significant structural commonality' a little.

Do you know of any a1-selective depressants that don't contain this feature? I can't find any.

You are right about amides (be them right out in the open a la meprobamate or hidden like a benzo) in GABA-A modulators,

There are hardly any depressants/anticonvulsants seen without this structure. Breviracetam, carbamazepine, ethosuximide, felbamate/ethinamate/meprobamate, Barbs, benzos, mephenoxalone, bromisoval, methaqualone, valerian-derived chems, beclamide, etc. It shows up enough that I think it can be viewed as a neccessity for GABA-A affinity. It's not 100%, of course, but damn close.
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The most interesting drugs are those with a triazolo ring- Alprazolam, CL-218,872, etc.

It seems to be able to substitute for the amide usually seen. Mattpsy kindly posted an overlap of Alprazolam and CL-218-872, and they line up really well.

It would be cool to see that tried on Methaqualone or Seconal or some other depressant. Even more interesting would be how well it works if it replaced the amide on Zolpidem or Zopiclone.

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I should also say that it seems that a-keto-T's were found to be depressants, as well, although AFAIK, nothing was published. A patent about their use as anti inflamatories was cited in the original patent of Zolpidem. That's what it seems anyway. I can't find any confirmation of that, though. It just seems rather likely, imho.