Exogenous ligands whose functionality acts upon endogenous ligands directly.

[Nagelfar]

By which I mean, a drug made that's a ligand which 'neutrally' binds to a site on a receptor, transporter or such; which is separate from the normal active binding conformation/site of another, natural and native ligand to ones own body. But the exogenous molecule's affect is wholly mediated by its chemical reaction to the endogenous molecule when it binds to its usual site of activity.

The example that follows is gleaned from my own limited understanding of how such specific mechanisms may be precluded from actually having such function: and so may be not the best for what I am here trying to convey if possible, but perhaps another may understand what I am trying to get at and have a more viable possibility:

Here's my "example" in the form of a rhetorical question:

If 'nanoparticles' can be used to treat molecules to pass through the blood-brain-barrier, might they also be used to slip molecules from their transporter system without compromising said transporters? (e.g. "compromising" as would be the case in phosphorylation caused by amphetamine on DAT) For instance, a reuptake pump ligand on DAT that doesn't block reuptake but rather alters the DA that crosses, as it crosses, DAT's uptake by said ligand eliciting (or similar) the addition of nanoparticles to each crossing DA molecule when attached to the pump which would impart the ability for DA to freely transport out of DAT immediately. Without thus effecting the other monoamines & also while not effecting DAT itself, but allowing DA to "self-release" on its own volition from that previous influence of an external molecule that is an intrinsically non-toxic ligand to an overlapping site.

 

[Sturnam]

I'm pretty sure you're talking about allosteric regulation, but to be honest I'm a little confused at exactly what you're asking for.

Anyway, positive allosteric modulators don't have any effect on their own, but can increase the response from the natural ligand. A good example is benzodiazepines, or alternatively, the newer AMPAkines.

 

[ebola?]

By which I mean, a drug made that's a ligand which 'neutrally' binds to a site on a receptor, transporter or such; which is separate from the normal active binding conformation/site of another, natural and native ligand to ones own body. But the exogenous molecule's affect is wholly mediated by its chemical reaction to the endogenous molecule when it binds to its usual site of activity.

This is put pretty confusingly, but if I understand you correctly, these classes of drugs sound like a long shot. An exogenous drug that binds to an endogenous ligand is likely to alter the shape of said ligand enough to disrupt activity in a variety of ways. To take your example, any change to DA that affects activity at DAT will likely affect activity at DA receptors.

the addition of nanoparticles to each crossing DA molecule when attached to the pump which would impart the ability for DA to freely transport out of DAT immediately.

I don't really get this. Molecules (hell, up to the size of polypeptides) are a lot smaller than "nano-particles". The addition of such particles will likely fuck up binding to anything.

ebola

 

[Limpet_Chicken]

Perhaps esterase inhibitors might fit the bill, in terms of being closer to the concept of solely mediating a drugs action through binding to and interacting with an endogenous ligand (albeit the target will be tertiary then, for instance, inhibition of MAO-b leading to decreased catabolism of DA)

Generally nonrecreational I would think. Out of such compounds I have tried personally, MAO-a inhibitor harmaline+harmine was not recreational, nor were an enkephalinase inhibitor, either of the two acetylcholinesterase inhibitors I have tried, galantamine and huperzine-A, both were simply functionally enhancing, and would be downright hideous in overdose (think 'nerve agent').

 

[ebola?]

The question is of molecules that directly affect endogenous LIGANDS. Esterases aren't ligands for specific receptors. Maybe there could be antagonist compounds that temporarily denature ligands.

ebola

 

[twoci]

"Ligand" is a very broad category. It's naive to talk about "denaturing" ligands because that implies the ligand in question is a protein. The reason it is uncommon to target small molecule ligands is specificity. How do you ensure that only the specific ligand you are interested in is modified? On top of that, you have to consider enzyme kinetics. That is, your Ligand+Drug reaction must be significantly (orders of magnitude) faster than the competing reaction (Ligand+Enzyme). These problems make this a very unlikely target.

 

[Nagelfar]

Molecules (hell, up to the size of polypeptides) are a lot smaller than "nano-particles".

It was a bad, solely analogous, example from something I had read elsewhere as being viable, but not in this instance.

...The reason it is uncommon to target small molecule ligands is specificity. How do you ensure that only the specific ligand you are interested in is modified? ...

This is why I am bringing up what I suppose would be, as Sturnam mentioned, an allosteric site for the exogenous molecule. So the exogenous ligand would be forced into a position due to its affinity with the allosteric site to come into a specific conformation of contact with the endogenous ligand; perhaps changing the endo-ligand into something that otherwise couldn't cross the BBB, but having it already there and at its site to have an immediate effect before being actively transported out or similar.

 

[twoci]

Such a weak interaction is going to be much less favorable than the interaction with the protein, it wouldn't work.

 

[Nagelfar]

Such a weak interaction is going to be much less favorable than the interaction with the protein, it wouldn't work.

I suppose at least a few & far between scenario? I do see the potential of two molecules having affinity to separate but locally adjacent sites on a protein, so that they'd have a consequent forced overlay when bound at their respective other domain to said protein which may be the only example of such a transfer/influence possibility.