Troparil and Dichloropane, chemist looking for serious answers...

[serotonin2A]

The fact that it influences only non-dopaminergic neurons was the basis for my thinking that it added to efficacy of it's influence as a reuptake inhibitor; i.e. electron energy resonance via electron clouds on the *quantum* level. Na+ channel blockers block the channel, a static/tribo-electric exchange of resonant energy once docked as a ligand at the reuptake pump at DAT where DA itself is influenced by the electron cloud from it's Na+ blocking ability at *non*-DAT sodium channels "on the way to" DAT reuptake ligand site and having garnered electron resonance energy from channels elsewhere on the way there.

I really don't understand what you are describing here, but DA doesn't block sodium currents.

 

[Nagelfar]

I really don't understand what you are describing here, but DA doesn't block sodium currents.

Yes, but DA is blocked physically by a DAT reuptake inhibitor *That Does*.

Think about it.... electron energy resonance. Exchange. Electron clouds.

 

[d1nach]

I'm pretty lost this is above me lol. I was thinking more along the lines of sodium channel blockades maybe working like PCP or ketamine

 

[serotonin2A]

Yes, but DA is blocked physically by a DAT reuptake inhibitor *That Does*.

Think about it.... electron energy resonance. Exchange. Electron clouds.

I understand the words -- it is how you are stringing them together that doesn't make sense. You ended the post with a long run-on sentence that is very confusing.

Let's take the first part of the last sentence:

Na+ channel blockers block the channel, a static/tribo-electric exchange of resonant energy once docked as a ligand at the reuptake pump at DAT...

DAT can conduct Na ions, but DAT is not a sodium channel, so it makes no sense to say that DAT reuptake inhibitors are "Na+ channel blockers".

Another issue is that binding to DAT does not involve "a static/tribo-electric exchange of resonant energy". You seem to be proposing that DAT and the ligand exchange charges due to frictional contact or some exchange of resonant energy, but that isn't how binding occurs.

And the second part:

...where DA itself is influenced by the electron cloud from it's Na+ blocking ability at *non*-DAT sodium channels "on the way to" DAT reuptake ligand site and having garnered electron resonance energy from channels elsewhere on the way there

First, it isn't clear whether what you are proposing happens inside or outside of cells. Second, DA doesn't block Na channels. Third, how exactly would DA "garner electron resonance energy from channels elsewhere on the way there"? I'm assuming you are talking about some type of ion channels, but I don't understand why you think there would be some type of interaction between DA and ion channels? Are you describing a situation where DA binds to receptors, which in turn can open or close ion channels, leading to currents that somehow interact with DA?

 

[sekio]

electron energy resonance. Exchange. Electron clouds.

these are just buzzwords to me. "resonance" of any sort is not involved in binding to GPCRs

 

[Nagelfar]

DAT can conduct Na ions, but DAT is not a sodium channel, so it makes no sense to say that DAT reuptake inhibitors are "Na+ channel blockers".

I am *not* saying that. I am saying that cocaine is, and a DRI. (obviously).

Another issue is that binding to DAT does not involve "a static/tribo-electric exchange of resonant energy". You seem to be proposing that DAT and the ligand exchange charges due to frictional contact or some exchange of resonant energy, but that isn't how binding occurs.

I am not saying that either. I am saying sodium channel blocking is blocking the action potentials of nerve firings (salt in a wound exacerbates pain sensation, local anesthetic stops it; stops the voltage gated channel), and that electron resonance energy goes somewhere; the blocked voltage gated Na+ channel for a sodium channel blocker (i.e. cocaine); which, also being a DRI, binds to the ligand site, where DA would go, and DA contacts the bridged ligand; and energy exchange thus; DA and electron clouds then go to their receptor site.

And the second part:

First, it isn't clear whether what you are proposing happens inside or outside of cells. Second, DA doesn't block Na channels. Third, how exactly would DA "garner electron resonance energy from channels elsewhere on the way there"? I'm assuming you are talking about some type of ion channels, but I don't understand why you think there would be some type of interaction between DA and ion channels? Are you describing a situation where DA binds to receptors, which in turn can open or close ion channels, leading to currents that somehow interact with DA?

I think I explained it in my above to response, what you don't seem to be understanding is my postulation about how *cocaine* specifically, being a Na+ channel voltage-gated action potential obstacle, and being a DAT ligand, might produce electron energy resonance that contacts with DA on its pathway. Anything further I need to clarify with this theory?

e.g. cocaine goes through the body, whether insufflated, injected, etc. Garnering electron energy resonance in contact with the action potential firings as a NA+ channel blocker, once reaching the ligand site at DAT; this has accumulated electron energy resonance, and unique affect as a DRI may be posited via such mechanism.

 

[serotonin2A]

I am *not* saying that. I am saying that cocaine is, and a DRI. (obviously).



I am not saying that either. I am saying sodium channel blocking is blocking the action potentials of nerve firings (salt in a wound exacerbates pain sensation, local anesthetic stops it; stops the voltage gated channel), and that electron resonance energy goes somewhere; the blocked voltage gated Na+ channel for a sodium channel blocker (i.e. cocaine); which, also being a DRI, binds to the ligand site, where DA would go, and DA contacts the bridged ligand; and energy exchange thus; DA and electron clouds then go to their receptor site.



I think I explained it in my above to response, what you don't seem to be understanding is my postulation about how *cocaine* specifically, being a Na+ channel voltage-gated action potential obstacle, and being a DAT ligand, might produce electron energy resonance that contacts with DA on its pathway. Anything further I need to clarify with this theory?

e.g. cocaine goes through the body, whether insufflated, injected, etc. Garnering electron energy resonance in contact with the action potential firings as a NA+ channel blocker, once reaching the ligand site at DAT; this has accumulated electron energy resonance, and unique affect as a DRI may be posited via such mechanism.

Ah, OK, I think I understand. However, there is no physical basis for what you are describing. Action potentials don't contain any type of energy ("electron resonance energy" in your terminology) that could be transfered to other molecules or that would have to "go somewhere" or dissipate if an axon potential is blocked. Axon membranes are excitable because they contain voltage-gated Na+ channels. Action potentials propagate because once the channels open, the inrush of positively charged sodium ions triggers neighboring channels to open. That process ends up repeating over and over again, creating a wave of depolarization that continues until it finally reaches the end of the axon. But if the sodium channels are blocked, there isn't any "energy" that has to dissipate -- the only remnants would be a few extra sodium ions in the axon, but those ions would be quickly pumped out of the axon by Na/K-ATPase.

Cocaine and dopamine also wouldn't be in contact around DAT. Once cocaine binds to DAT -- making the substrate binding site inaccessable -- then that particular DAT molecule would be no more attractive to dopamine than any other membrane-bound protein. So once access to the substrate site is blocked by cocaine, the only dopamine near DAT would be dopamine in solution. But even if they come in contact in solution, there isn't any type of energy that either dopamine or cocaine could accumulate and transfer to each other.

 

[Nagelfar]

Ah, OK, I think I understand. However, there is no physical basis for what you are describing. Action potentials don't contain any type of energy ("electron resonance energy" in your terminology) that could be transfered to other molecules or that would have to "go somewhere" or dissipate if an axon potential is blocked. Axon membranes are excitable because they contain voltage-gated Na+ channels. Action potentials propagate because once the channels open, the inrush of positively charged sodium ions triggers neighboring channels to open. That process ends up repeating over and over again, creating a wave of depolarization that continues until it finally reaches the end of the axon. But if the sodium channels are blocked, there isn't any "energy" that has to dissipate -- the only remnants would be a few extra sodium ions in the axon, but those ions would be quickly pumped out of the axon by Na/K-ATPase.

Cocaine and dopamine also wouldn't be in contact around DAT. Once cocaine binds to DAT -- making the substrate binding site inaccessable -- then that particular DAT molecule would be no more attractive to dopamine than any other membrane-bound protein. So once access to the substrate site is blocked by cocaine, the only dopamine near DAT would be dopamine in solution. But even if they come in contact in solution, there isn't any type of energy that either dopamine or cocaine could accumulate and transfer to each other.

Aren't there pockets of solution around DAT ligand binding sites? I think I read something along such lines. Perhaps a stretch:

Mainly I am looking for something to do with ions that would influence the effect that may cross over as another explaination than "inverse agonism" (I am quite aware that many non-local anesthetics have this same mechanism, e.g. methylphenidate, but not seemingly to the same degree as cocaine). Would a substrate size molecule be able to be made a Na+ channel blocker (kept that small and still function?) or possibly a dopamine direct agonist, also be made a sodium channel blocker, to see what effects there are? *This* is what I mean by there needs be further study.

Example: the "spirocyclic tropanyl-Δ(2)-isoxazoline" allosteric DAT modulators (cmpd 11a for DAT, and 7a for SERT) that change the conformation of the MATs to accept more reuptake ligands. Could something like that be at work? The shape is very close to the cocaine molecule, and was discovered tinkering with it. Same with the eta-coordinated phenyltropane chelates; which have long-standingly been called conformational, and now, due to this anomaly, called an electro-static consideration in this instance, oddly see the Cr(CO)₃ ''versus'' Cp*Ru

EDIT: I also remember reading that mice who were habituated to cocaine administration showed euphoric/stimulation response to non-stimulant local anesthetic (e.g. lidocaine) over placebo. I notice this myself when injecting small amounts of local anesthetic to see if I felt stimulated and I did; before I got to any sort of dose where my body felt numb or numb at the injection site, some kind of sensitization must be at work in minue amounts, something in the CNS.

 

[Nagelfar]

Looking at other (old) pages, a moderator was walking about the para-chloro-PT (i.e. RTI-31 of the Coc/4229 series)

It's supposed to be 10x cocaine's potency, and 64 times more addictive. I.e. Active at <1mg.

5mg could potentially be fatal.

Anyhow, I also (as above linked topic in quoted name postulates) that those who claim to have "gotten Troparil" and found it 'disappointing' were most likely deceived. Upon closer consideration.

 

[izo]

Ive Heard the same effects from three different people now of Troparil. Had around 25-30mg 2 times myself and every time the same happened. After 5 minutes of rectal dosing I get slight effects. Not really stimulating but rather calming. Then the elbows feel kinda wobbly, not really pleasant but it’s only the elbows, no other joints. And then after about 15 minutes you feel kinda tired, so tired that you have to lay down for some time. You immediately fall asleep for about 15minutes and after that you wake up and some of the activity persists for about 1 hour. That’s about it, was exactly the same for all 3 that tried this and I didn’t found it to be rather enjoyable or useful. Any ideas about any other other phenyltropanes from the rti class? Don’t think any of these has any real potential…