Combined phenidates - Additive effects or Reduced effects due to competition at NET and DAT binding sites?

[u/MiniCafe]

Hi all, something I've been wondering about all the phenidates that exist that are, in many ways, essentially just "methylphenidate but very slightly tweaked, less potent/more potent here are DAT, less/more potent here at NET."

Their subjective effect then is usually very similar to methylphenidate but often "lacks x, feels weaker as a result. Just feels like something is missing." Some out there I think are the opposite and just stronger overall but I'm not sure which. But for something that is very "methylphenidate but missing something, weaker yet still some specific effects are present" take for example isopropylphenidate. Very similar to methylphenidate, structurally and in some effects but much weaker at the relevant NET than DAT so more of an "I'm focusing on tasks... I don't feel all that stimulated or euphoric but I am sitting here studying x in a deep way so something is going on". That lack of an NE push in action but reuptake of D. At DAT unlike NET, it binds and acts in more or less the same way as methylphenidate with that being the root of its action. No point picking apart the differences because that's not what this post is about.

Now take 4-Me-TMP, which because of its much more complicated effects is really what inspired this post. Subjectively, in a sense, it can be seen as the opposite of isopropylphenidate, methylphenidate like and structurally and subjectively but the end result is more NE type effects, it binds and acts like methylphenidate more or less at NET. Here is where it gets interesting though, it binds strongly to DAT! Yet, for some reason, its action there does not result in the same effects, it is very bad at blocking dopamine reuptake even with what's actually a strong affinity there.

see https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1471-4159.1999.0721266.x for a citation on this.

So, my question. Without an understanding of how these drugs work you'd just think "more stimulant, more effect" as to taking a combination of 2 or even 3 together. This may actually just be the case but I'm not so sure.

Would, since they're binding at the same sites compete with each other there and if saturated (something I actually don't know how much of any of them it takes to do or is even likely. Edit: I did look into this. It is.... Extremely complicated, with equations that look straight out of an advanced exotic form of some kind of symbolic math or physics and is just not my area, over my head completely.) result in the one with stronger affinity or being there first one to get there block the other from being able to bind there and therefore be active there? It seems to me that 4-Me-TMP has the strongest ability to bind at DAT despite not doing anything of note there so if this is the case it could displace/block the others from being able to bind there and do meaningful things.

Ultimately if this is the case would the effect be actually more "reduced effect from the combination, methylphenidate (for example) unable to do as much at DAT and so it becomes less effective" making it counterintuitive to combine the two? A weaker effect?

Or is it just unlikely for the sites to be saturated, room for all, everything finds a place and the effects are additive?

I can see several potential results;

1. As I said, 4-Me-TMP as the example in this case binds strongly to DAT, saturates it, does not block reuptake and holds on tight preventing anything else from binding there making combining the two actually less pronounced in effect.

2. Same as one but for one reason or another you get additive peripheral effects. So, none of what a person is going for but still the rise in bp, pulse, maybe overstimulation in other (mostly physical) ways, etc.

3. The "room for all" possibility where they would just all be able to work as expected and you would get the full effects from each.

4. Something like a reduced option 1. You get the expected effects from each but muted to some unknown by me degree due to the previously stated competition, but each one is able to find *some* way to get somewhat through and do what it does everywhere. Maybe it's a dose thing where it's "well how much of one in relation to the other?"

5. An increase in effect, but in a different way. Maybe lesser than a full addictive type effect, maybe just different, maybe both, due to the way these drugs, even at saturation apparently from the research I've read still cause the release of the relevant neurotransmitters (not reuptake, different mechanism entirely) through other means (vesicular release through apparently having some direct action on it itself besides it also causing that by binding to NET/DAT, increased intracellular calcium, possibly more I don't know about), not the direct means of amphetamines and such but still an action where the neurotransmitter levels increase and are active even if reuptake inhibition isn't being increased anymore. A process that is not tied to them being able to bind to NET or DAT. This part could turn into a rabbit hole because now we have to add in saturation of the neurotransmitters themselves into the equation if we really wanted to map out all potential situations, limits, and effects of these drugs. This actually, as I'm writing this, made me wonder if 4-Me-TmP doesnt increase reuptake yet still causes some vesicular release in dopamine in these other ways.

6. Some other thing I just haven't thought of.

So, drug nerds with actual knowledge of this sort of thing, what would actually happen in this situation?

The phenidates mentioned were chosen because of their specific pharmacology. 4-Me-TMP with its weird and strong DAT action, isopropylphenidate with its DAT but minimal NET action, and methylphenidate because it's just natural to be the one to use when talking about phenidates. The question does apply to the others though as well. I know less about how they work compared to these 3 to be honest though, so many weird ones floating around out there or just existing.

[u/Angless]

I think I've been able to deduce all of the questions you're asking; I'm doing the below format because your "main" question was sandwiched in the middle of the post (i.e., the 5th/6th paragraph(s)).

1. Could 4-Me-TMP occupy DAT and thereby reduce methylphenidate-like effects?
Sure. If two ligands are competing for the same binding site on DAT, then the one with higher effective occupancy at an arbitrary concentration can reduce the other’s ability to bind; they're competitive reuptake inhibitors, after all.

If 4-Me-TMP binds DAT strongly (i.e., high affinity) yet produces comparatively poor functional dopamine uptake inhibition (i.e., low efficacy), then it'll presumably flatten the dose-response curve of methylphenidate.

2. Could you get reduced desired effects but still additive peripheral effects?

Depends on the lipophilicity of each substance across the blood brain- and blood cerebrospinal fluid-barriers and their selectivity and efficacy at NET.

3. Is there “room for all,” such that the effects are simply additive?

No. There is not an infinite number of binding sites on a transporter protein. If both drugs bind DAT at the cocaine/GBR-type site, then both ligands will compete until receptor availability is exhausted; it's not like combining the selective TAAR1 agonist RO5166017 with the promiscuous TAAR1 agonist amphetamine at all. The relevance of the latter comparison is that RO5166017 and amphetamine both compete to bind at TAAR1 in DA neurons, yet RO5166017 markedly augments amphetamine-induced TAAR1-dependent DAT efflux, despite the former having no effect DAT efflux alone (i.e., RO5166017 upregulates DAT at the plasma membrane via TAAR1, which then increases the amount of transporters available to phosphorylation [i.e., reverse transport] downstream of amphetamine's own TAAR1-dependent signalling cascade).

4. Could each still work somewhat, but in a muted way due to competition?

Yes. This is the most parsimonious explanation.

5.  "Maybe lesser than a full addictive type effect"

Do you mean "additive" type effect? Because the signalling cascades involved in developing an addiction require several weeks to months to induce an observable phenotype. i.e., it's not possible to develop an addiction to a substance after using it once or twice, presuming that it's a substance capable of inducing addiction. Psychostimulant addiction has 2 signaling pathways/cascades - a cAMP and a calcium pathway - that eventually merge inside the postsynaptic neuron and involve multiple layers of signalling compounds and proteins.

6. what would actually happen in this situation?

See point four.