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The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

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UR-144 feels like low mids... stony body buzz, sedating, gives the munchies hardcore, but nothing too "WHOA" mentally (though there is a bit of a head high). UR-144 is "creeper" as well
 
Hey, I'm just wondering.

What would ketamine be titled in the PCP / 3-MeO-PCP / 3-MeO-2-Oxo-PCE / etc. nomenclature?
 
Ketamine contains neither the PCP nor the PCE skeleton (it contains a methylamino group rather than an ethylamino group, and of course only 2 ring-systems), so this nomenclature doesn't really work for it.
 
But if one were determined to refer to it in such terms, 2-chloro-2'-oxo-PCM would be as good as it gets.
 
When a carboxylic acid reacts with an amine, why is it that a covalent bond is formed and not an ionic one?
 
In short, the difference in electronegativity is not high enough.

There is a degree of ionic bonding and covalent bonding in every bond, but the difference in electronegativity governs which is dominant and therefore which we call it.

Carbon doesn't form ionic bonds often at all, except in combination with a few metals, and these are unstable.

As a guide, the closer two atoms are in the periodic table, the more covalent their bond will be.
 
I recently had a taste of 2-(3-methoxyphenyl)-2-(methylamino)cyclohexanone which I talked about on the previous page.
(Methoxetamine with a methylated amine - one could call it N-methyl-methoxetamine for the lack of a better name)
 
re:N-methyl-methoxetamine - I remember reading that secondary amines are the way to go for ArCHAs - viz. phencyclamine (mild) vs eticyclidine (strong) vs dieticyclidine (weak, really a prodrug for eticyclidine) - making a tertiary amine gratly decreases activity (except it seems in the case of a pyrrolidine or piperidine subst).
 
I think repulse was talking about N-methylnormethoxetamine, not the tertiary amine.
 
Excuse me for dusting off some old threads but I felt this was interesting. Are there any covalent binding agonists that bind to a receptor in a reversible fashion, i.e., the covalent bond is broken before the receptor is internalised? It'd definitely be possible to design proteins with this property to specific ligands. But the cost of making and breaking covalent bonds (entropic vs. enthalpic) may make this a rare mechanism in nature given that the noncovalent solution works (what is fraction of covalent binding agonists relative to all agonists?).


MattPsy said:
If something is a suicide substrate (like a covalently binding agonist) then eventually receptor internalization will occur (and the receptor is replaced eventually). However until internalization occurs signal transduction can usually still take place so the effect of an irreversible agonist is not that of an antagonist, effectively, because the receptor population is not immediately destroyed.
Click to expand...
 
I think you hit the nail on the head: traditional SAR isn't good enough to identify/design a ligand with the selectivity you want. If it is boiling down to hydrophobic vs. polar, i.e., hydrophobicity is obscuring the signal in picking/designing a ligand that is selective for DAT but not for NET, then it needs to be controlled for. Doing it with the current best computational docking methods would be more accurate and selective. How about computationally screening every known human ingestible compound against both DAT and NET and identify ones that have high affinity for DAT and low affinity for NET,? Someone's already doing this it looks like.

So I take it that the original point was to design a SDRI (or SIDRI - for the indirect kind)? I agree you could work on NAChR instead of DAT. In fact, it'd be interesting to examine what happens with DA vs. NE with all the current NaChR agonists available. (As an aside I hadn't pondered this, but NaChR is similar to GABA A so it's possible to see how a GABA modulator can also effect DA levels.)

Another way to be to have a ligand that decreases the number of DATs expressed or translated either directly or indirectly. This probably will have effects you don't want too so it's a messy way of doing it (though it gets around the oily ligand problem). But is this that different from a DRI that works by indirectly internalising DAT?

And then you can create a leaky channel like AMPH does and make DAT go from symporter to antiporter.

There are reports of compounds in animal models and preclinical studies that have higher selectivity to DAT compared to NET or SERT.

I would turn the question back on the OP. What can you do to take a ligand that binds both DAT and NET and modify to make it selective to DAT and nonselective to NET? (I'm asking from a atomic interaction perspective---when you look at the structures of DAT and NET and the binding sites, what can you distinguish?)

--

Another way to think about this is in terms of modulating currents upstream of the dopamine release. Dopamine gets released based on a particular voltage signal the neuron it is in receives (I'm not a neurobiologist so please excuse me if I'm not being technically correct and I would appreciate it). The amount of modulators immediately upstream of DAT is in the order of tens of thousands. Apparently it has been shown that the rate and direction for DAT itself is totally dependent on the Na gradient which is controlled by a Na+/Ka+ ATPase. It's probably not a good idea to directly mess with this sodium pump (unless there's a specific isoform that controls the DAT gradient) but there's probably things upstream that let you control this pump indirectly.

--

This is a good idea BTW. Whoever can design a SDRI may contribute a lot to this world in many ways. I concur with EA; there are a lot of ways to accomplish this.

Epsilon Alpha said:
So this is during a coffee break before a lab so bear with:

Well most of the problem comes from the fact that using traditional SAR, as things become more selective for DAT vs NET it also starts to bind to other things, for example meth vs regular amp. DAT just loves those oily mofo's.

But what I was getting at is the PKC mediated releasing action really isn't that different for NE vs DA, so using the traditional amphetamine MOA isn't ever really going to give you a greater DA/NE ratio. However, for reuptake inhibitors or things that bind to things like 5ht3 or NAChR there is a strong possibility for making a "selective" indirect DA agonist.

I'll post more when I have more time.
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ebola? said:
Aha! Another piece of the puzzle that I didn't understand. So amphetamine-like efflux is achieved by the exogenous ligand inducing PKC to phosphorylate the transporter (by binding to PKC, changing its conformational form?). Okay, so if this mechanism is fundamentally similar whether we're talking about DAT or NET, why do releasers have any selectivity at all? Are there different isoforms of PKC present proximate to different transporters?

ebola
Click to expand...

I don't see why "DAT and NET are similar" leads to "no selectivity at all can be achieved by those transporters." These graphs seem to imply different transporter affinities for the different amphetamines, since they're graphs of transporter uptake activity. I don't think that by the methodology used in the study would be confounded by release, since the transporters were studied in intestinal cells which I assume wouldn't don't express PKC. As you'd expect, meth has a much higher relative inhibitory ability at DAT over NET as compared to amp.
I don't know to what extent you can extrapolate from inhibitory efficacy to general affinity for the transporter, because I assume the extent to which they act as substrates rather than inhibitors varies. But in any case the way that each agent acts on DAT as compared to NET does very between the individual amphetamines.
http://www.biomedcentral.com/1471-2210/6/6/figure/F1
Full study:
http://www.biomedcentral.com/1471-2210/6/6
 
Ah. Very good study. So it looks like various other factors affect the ability of amphetamines to phosphorylate the receptor. So theoretically, one could manipulate them to engender a very high degree of selectivity.

ebola
 
You guys interested in making a thread out of the NE/DA efflux ratios topic?
Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.
 
Er...it's actually releasers where the topic becomes interesting; we've already developed highly selective DARIs.

ebola
 
bluedom said:
If you have selective DARIs then what is the need for the releasers?
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There's no actual "need" for them in the market, but its interesting as sin to discuss and who knows where the conversation will turn. Someone post the OP and I'll get around to the new thread by Sunday.
 
Epsilon Alpha said:
Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.
Click to expand...

From skimming wikipedia, it doesn't look like they do.

bluedom said:
If you have selective DARIs then what is the need for the releasers?
Click to expand...

There's no guarantee that they'll act as similarly as NDRIs and NDRAs, between which there are already big enough differences that one might want to use one instead of the other :p
Just speculating, since alpha 1 receptor activation increases basal dopamine release IIRC then maybe selective DRIs have a low ceiling of efficacy which DRAs might not have.
 
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