I Like to Draw Pictures of Random Molecules

[roi]

Inspired by pregabalin

 

[adder]

@Solipsis

Your reasoning with binding energy sounds right. I later saw the comment by serotonin2a you're quoting and that made me thinking as well.

Also I wouldn't think that affinity has nothing to do with dissociation time, because if there is more optimal binding energy (difference between intermediate state with bound/unbound state) doesn't that lead to longer dissociation time since that energy is not so easily overcome? It seems like that would mean that it would at least be one of the factors if not the only one in net displacement since even if one or the other ligand does bind 'better' than the other one, when the long-occupying one IS actually bound to it, during that time there is no competition possible.

So now I'm wondering what makes fentanyl have a higher affinity than buprenorphine but at the same time dissociate much faster from mu receptors. I suppose you can explain everything in terms of energy, but affinity then can't be just the only thing affecting dissociation time, there must be a way for molecule A to bind with a higher energy but at the same time unbind more easily than molecule B which binds with somewhat lower energy and stays bound for longer, and that might be dictated by the nature of component interactions and conformation changes they cause, though I don't really know how it would work out with such big systems like receptors.

 

[Solipsis]

Reading up on it, I think that the reason for that is that it's not a first order process of ligand and receptor forming a complex in one reaction process, but an induced fit: the initial binding of the ligand to the receptor causes an isomerization, a change in the conformation that changes it into a usually higher affinity final complex, that causes the ligand to have an extended residency time (occupation).

In such cases affinity is not a simple = (1 / dissociation time), but becomes a multivariable of association time and dissociation time, which are functions of the energy of more than one state of the complexed or not receptor.

VVV the induced fit causes the thermodynamics to shift, which would explain different energies and times for association and dissociation

I am not positive if the below example applies exactly in terms of how the shift occurs.

NSFW:

 

[Bagseed]

I was thinking about this recently. I have no clue about this though, any thoughts?

 

[Nagelfar]

^
RTI-(4229)-163/157 + 220c + ebati, p-azido,m^3′-nitro,m^5′-nitrile-phenyltropane

In such cases affinity is not a simple = (1 / dissociation time), but becomes a multivariable of association time and dissociation time, which are functions of the energy of more than one state of the complexed or not receptor.

I've been wondering about the variable of entropy of binding kmol values recently in terms of how that effects abuse potential, e.g. between cocaine & methylphenidate. Is there no known predictor for such a thing besides direct observation comparing two ligands?

 

[blueberries]

Ok, I've got a bit of a mash-up here; 5-Fl-a,N,N-TMT

The base compound a,N,N-TMT is active at 80-120mg, 5-Fl-aMT is supposedly quite a powerful compound in itself, being an SNDRA and 5-HT2a agonist, plus 5-Fl-DMT has little effect on the base compound's psychoactive effects, so the addition of the dimethyl would have no effect upon the 5-Fl-aMT. Altogether it should be quite an impressive compound...if not for the MAOI properties of aMT. So you'd need to be careful but I was thinking that either a 5-Tri/Fluoromethyl or 5-Fluoro-methoxy group would serve to first off increase potency and secondly perhaps reduce the MAOI properties but the latter is a complete guess!

 

[Nagelfar]

lol

This one I didn't even make up, puts mine to shame:

A methylphenidate cross between Adiphenine & Dicycloverine (possible inhibitor of nicotinic or muscarinic receptors + inhibitor of DAT?)

 

[blueberries]

I just thought of this too:

4-Acetylthio-DMT; I'm very doubtful it would work at all but it's an interesting thought nonetheless.

 

[Midnight Sun]

Pretty sure something just like this has been posted already a few pages back, but whatever...

As far as this thing goes, I was paging through aced's thread about DRI pharmacophores and I could've *sworn* I read once upon a time that esters were more critical to DAT binding than anything else... but now I can't find anything referencing that. shit looks more like a weird reverse-o-matic take on meprobamate I'm not even sure if that structure is permissible anyway

 

[Bagseed]

This one I didn't even make up, puts mine to shame:

the main problem with your compound is that sp2 hybridized carbon atoms have all their bonds lying in a plane. so you cannot have this nitrogen sticking over the ring plane being bonded to it.

ps: I'd really like some feedback on my molecule.. has this been tried before? I thought since beta-keto doesn't destroy activity, replacing the beta carbon with an ether might be something worthwhile...

 

[aced126]

I think the amine has to be in the plane of the phenyl ring for greatest efficacy at DAT. This is how it is in dopamine and in amphetamine (antiperiplanar conformation) but I don't know if this is the case with this molecule. There's a good chance it'll work well as a dopamine releaser though with a shorter half life (the ether is an alright metabolic handle).

 

[Bagseed]

I think the main difference between C-O-C and C-C-C is the bonding angle, the rest should be fairly similar (regarding configuration).

I also thought about metabolism: should give phenol (yuck) and 1-Aminoethanol, no?

 

[pharmakos]

seems like a pretty easy group for enzymatic attack in your body. but idk enough to say for sure... anyone else?

 

[Bagseed]

yeah I am no good at pharmacology, that's why I posted it here

 

[pharmakos]

just judging based on my layman's feels, tho, any simple group like that aminoethanol group is going to be pretty easy for one of your body's enzymes to hit. if it even needs to hit an enzyme before separating from the benzene... maybe just acidic conditions could do it? idk. still just *looks* fragile to me. like it's barely holding on. =p

 

[Bagseed]

:D

but to be fair, you find plenty of ether groups in very active compounds (methoxy groups), and they don't seem to fall apart very quickly.

 

[pharmakos]

true story. i had half a thought typed up about that, i think the nitrogen makes a pretty big difference, but i typed half the thing calling aminoethanol an amino acid and only realized at the end that it isn't in fact a true amino acid, so i scrapped that whole train of thought. =p

 

[aced126]

When considering metabolic products, it's good to take into account what the likely dosage of the compound will be. Given that the ether is active sub 100mg, the amount of phenol generated from metabolism shouldn't be enough to cause harmful effects like DNA alkylation etc.

 

[aced126]

Ethers are strong bonds. I didn't mean to say that the compound would be easy to metabolise when I said the ether could function as a metabolic handle. I meant to say that it gives the compound another possible place of metabolic attack, which in general is good for the safety of the drug as the liver can attack it in many ways. A straight carbon-carbon alkyl bond will not be metabolised at all (unless it's got electronegative substituents of course) but ethers can be metabolised slowly.

What is a weak bond is an ester bond, which is easily hydrolysed in water along with acid or alkali as a catalyst. This is why drugs like cocaine have a very low oral bioavailability.

 

[blueberries]

Sorry to interrupt but I had an idea based on Shulgin's statement that fluorine atoms are essentially "fake" hydrogens, so if that were true, would NFl2 be able to replace amine groups? I always saw them as "fake" methyls, so I'm quite skeptical, but imagine the difference in affect, and this could apply to /any/ compound, perhaps changing it significantly.

Also could you take a quick look at my above compounds; I'm really interested in that acetylthio bit and the aMT one..well, it could be beautiful!
Thanks!