• N&PD Moderators: Skorpio | thegreenhand

A truly, equal across the board, SNDRI to rival cocaine?

binding values are more a measure of the affinity for the transporter, while potency is better described by reuptake inhibition, efficacy is defined as the maximal effect that a drug can induce in functional studies
 
Cocaine is thought to act like an "inverse agonist" at DAT. Binding studies provide one measure of potency for interacting with DAT, but they don't address whether a ligand actually produces cocaine-like effects.

I don't really understand how the term inverse agonist can apply to a transporter like DAT in a way that would distinguish it from a normal antagonist. If the molecule is bound to the protein and thus preventing substrates from binding, I don't see how also lowering its activity makes any difference, given that's it's not actually able to perform any actions during that time.

The only variation on monoamine transport blockers I can imagine wouldn't have effects identical to antagonists would be a drug that binds to the transporter permanently as an irreversible inhibitor. I'm not sure such a substance even exists currently, nor if any studies have been done to explore the possibilities and effects of permanently disabling various transporter proteins.
 
I don't really understand how the term inverse agonist can apply to a transporter like DAT in a way that would distinguish it from a normal antagonist. If the molecule is bound to the protein and thus preventing substrates from binding, I don't see how also lowering its activity makes any difference, given that's it's not actually able to perform any actions during that time.

The only variation on monoamine transport blockers I can imagine wouldn't have effects identical to antagonists would be a drug that binds to the transporter permanently as an irreversible inhibitor. I'm not sure such a substance even exists currently, nor if any studies have been done to explore the possibilities and effects of permanently disabling various transporter proteins.

If a drug reverses the direction of transport, so that dopamine is transported from the cytoplasm out to the synapse, then such an action would distinguish it from a typical antagonist.

Regarding your last point, there are certainly drugs that bind irreversibly to DAT. Metaphit is the first example that comes to mind...
 
But if it reverses the transporter, wouldn't that make cocaine a DRA rather than a reuptake inhibitor?
 
Absorption from blood to brain require that the molecule bears no charge so pKa VITAL
Distribution - The LogP governs how lipophilic the drugs (does it sit in watery blood or Fatty brain tissue.

Of course, you could RTFM yourself to learn this - or is this site devoted to those who can't to get those who can to do the work?
 
Absorption from blood to brain require that the molecule bears no charge so pKa VITAL
Distribution - The LogP governs how lipophilic the drugs (does it sit in watery blood or Fatty brain tissue.

Of course, you could RTFM yourself to learn this - or is this site devoted to those who can't to get those who can to do the work?

Once again, as has been pointed out several times, the question was about in vitro potency. ADME factors don't come into play until you move to in vivo.

In other words, binding, uptake, and release assays are usually run in little dishes or trays on a bench in some lab. Factors like absorption and distribution have no bearing on the results because cells or pieces of membrane are suspended in a buffer along with the drug.

Of course, you could just completely ignore these facts...
 
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Besides becoming a flame war between some of our otherwise usually very cordial and well-rounded/level-headed members (someone swap your morning coffee for decaf guys or what?) I still haven't got one single response presenting any compound that even approximates my simple inquiry; I mention this not as venting to any underlying frustration at the circumstance or it being construed as some personal slight (this thread has too much enough of that) but because I find this the very factor of the matter that no-one has furnished such to be a fascinating case..... Very possibly/Maybe not related to what the causal browser/lurker could chalk up to just tghe usual web forum TL;DR vacant stare omission of noninterest

...cocaine was pretty much the first chemical recognized stimulant, so SNDRI, or tri-uptake inhibitor became the staple gold-standard as a category and a heading for such types, and we shelved it away in our collective chemistry memory as such.... but the SSRIs, DRIs, NDRIs, etc, seem to be the rule over the exception... might it be possible that the fog of those academic chemists wanting to understand each stand alone monoamine transporter/receptor separately by way of finding selective compounds has made everyone not notice that cocaine, far from being the first of some wide gulf of a category ("SNDRI"), is actually something of a rarity in its spread of hitting those three (admittedly closely related but with all due respect to also note being structurally distinct enough for each one to be tersed apart from one another so much and so far so that they are left cleanly un-engaged/un-entangled from exogenous functions set to probe them by design?) neurotransmitter transporter sites as indiscriminately and as readily as it does?

Again, it's so blatant of a subject, it might be seen as a silly thing, but if so, wouldn't my task asking to present another able to say *one such other* drug by name would by now have some values/numbers thrown out in response?
 
I'm pretty sure most cocaine analogues will be presented in Singh's papers, and if none of them in those have an even ratio of reuptake, then there probably isn't one structure that exists at the moment that satisfies your conditions. However, with there being infinitely many possibilities for structures, I'm sure several yet to be synthesised analogues do exist with even ratios.
 
Cocaine is thought to act like an "inverse agonist" at DAT. Binding studies provide one measure of potency for interacting with DAT, but they don't address whether a ligand actually produces cocaine-like effects.

exactly what i was trying to say in my previous posts. if cocaine has a particular sort of interaction with DAT (which would make it different from 'regular' reuptake inhibitors like bupropion etc), then a drug simply with a similar binding profile wouldn't necessarily have similar pharmacodynamics...
 
How does the effect of cocaine at DAT differ from that of amphetamine and its derivatives? What about NET and SERT? Its activity at SERT is particularly interesting, because if cocaine's effects are as some in this thread have suggested - and it essentially reverses the transport direction at DAT - having similar effects on SERT would make it (at least at first glance) not at all unlike MDMA and related compounds.
 
How does the effect of cocaine at DAT differ from that of amphetamine and its derivatives? What about NET and SERT? Its activity at SERT is particularly interesting, because if cocaine's effects are as some in this thread have suggested - and it essentially reverses the transport direction at DAT - having similar effects on SERT would make it (at least at first glance) not at all unlike MDMA and related compounds.

One major difference is that amphetamines tend to redistribute transmitters from vesicles to the cytoplasm. It is one thing to reverse transporter action, but there is normally only a limited amount of transmitter in the cytoplasm, meaning that there is only some much DA/NE/5-HT that cocaine can move outside the cell. On the other hand, amphetamine can access transmitter stored in vesicles, which is a much larger pool.
 
How does the effect of cocaine at DAT differ from that of amphetamine and its derivatives? What about NET and SERT? Its activity at SERT is particularly interesting, because if cocaine's effects are as some in this thread have suggested - and it essentially reverses the transport direction at DAT - having similar effects on SERT would make it (at least at first glance) not at all unlike MDMA and related compounds.

I remember there was a user a long time ago (when I first joined, '07ish) who propagated the distinction of "coke back in the day" and gave the suggestion for washing the product today, and that a good dose of relatively pure product was subjectively like the peak of an "MDMA" 'roll' experience but smoother (more consistent) feeling.
 
If so, it makes sense that pure cocaine should feel like a milder version of MDMA.

I wonder though, does a compound exist that acts as a reuptake inhibitor or releasing agent for DA and 5-HT but not NE? It seems that for most people, the increase in noradrenaline is the cause of the majority of unpleasant side-effects (although I personally react pretty badly to most DRIs and DRAs, I suspect I'm somewhat of an anomaly).
 
If so, it makes sense that pure cocaine should feel like a milder version of MDMA.

Not "milder", actually like a longer peak of it (but shorter overall duration, of course)

I wonder though, does a compound exist that acts as a reuptake inhibitor or releasing agent for DA and 5-HT but not NE?

https://en.wikipedia.org/wiki/RTI-83

Remember however that DAT works for NE too if NET is insufficient for it, and via the natural metabolic pathway all DA becomes NE downstream. I thought some kind of alpha-blocker might attenuate this myself, but it hasn't been seen to be the case from what I've read of the colloquial experiences of others.
 
I've been having a field day adding new phenyltropanes (specifically their piperidine homologues) at the WP list of PTs page. It's once again looming over my coke analog page, threatening to dwarf it in size and scope. Though at least their both competing giants now.
 
Very nice WP pages indeed, I'll have to go through both of them in detail one day. Maybe a good idea is to look over all the structures and outline a summary of the SAR (e.g moiety X on carbon Y leads to ... ) and the overall pharmacophore of these sets of compounds.
 
Very nice WP pages indeed, I'll have to go through both of them in detail one day. Maybe a good idea is to look over all the structures and outline a summary of the SAR (e.g moiety X on carbon Y leads to ... ) and the overall pharmacophore of these sets of compounds.

Yeah, just added a bunch more from Singh's paper to the PT list, still have five kinds not yet on the WP page from his paper (N-modified, 8-oxa, 3-aryl bicyclo, 6/7 substitutions, and 7-substituted-3-butyl) probably another five to six hours worth of work at the library comp.
 
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