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

[Nagelfar]

I've been studying cocaine analogs for over eight years now, and I've yet to find one, phenyltropane, anything, that, with uptake inhibition measured by IC50, which is as close to cocaine in getting them all equally. Many have two of the three that are more close together; e.g. NE & DA, or DA & SER, or maybe even NE & SER; with an affinity in a more even proportion than R-cocaine, but the third is then way out there. None with all three as closely tersed have I been able to find. (this is by looking at direct inhibition of reuptake, not the displacement of another selective ligand, as those values can fall to pieces once compared with the reuptake of each monoamine directly)

Cocaine *is*

DA
241 ( ± 18 )

NE
160 ( ± 15 )

&

SER
112 ( ± 2 )

Meaning the selectivity between SER & DA is 0.5 & between NE & DA is 0.7

Can't seem to get it any closer, in the plethora of phenyltropanes and the like that have been elucidated, none come that close to a double "1.0 & 1.0" with selectivity.

If anyone can cite a publication of *anything* that does, please let me in on it, will you?

 

[clubcard]

LogP? pKa?

 

[aced126]

I don't think LogP and pKa is of concern in this situation as OP is not considering physiological effects (at least at the moment I think) but rather in vitro reuptake inhibition.

Besides, if a perfect ratio is achieved, then logP can be (somewhat) circumvented by simply increasing the dose. Obviously if the drug now binds to other targets around the body, that is a problem if logP is low.

 

[aced126]

Are you limiting the scope of compounds to phenyltropanes only? I'm sure I remember a few agents (not phenyltropanes) which are relatively equal in selectivities (methylphenidate derivatives come to mind).

 

[clubcard]

OK Amfonelic acid

 

[aced126]

source for ic50 values?

 

[dopamimetic]

Interesting that cocaine is stronger at NE than it is at 5-HT. Always thought that it was DA > 5-HT > NE. But when we think about the recently suggested 'inverse agonist' theory, that likely also applies to its 5-HT activity, it's a bit more difficult ...

Edit: But then also I'm not sure if we really need to closely replicate these values to get a worthwhile analogue. Probably an inverse agonist with anything of DA > 5-HT : or > NE could be nice ... ?

 

[neurotic]

if cocaine and the like release monoamines (transporter inverse agonism) then aren't IC50 values irrelevant?

 

[dopamimetic]

It's not direct releasing if I'm correct but amplification of the natural firing dependent release ... but then the values would still declare potency and overall character of the compound?

 

[serotonin2A]

Cocaine and methylphenidate have been proposed to be DAT inverse agonists, allowing dopamine to leak out of terminals.

In any event, the assays are measuring potency at blocking monoamine uptake into terminals. That gives you a measure of absolute and relative potency at each transporter.

 

[dopamimetic]

Yes, but there is a small but relevant difference between the real releasers (like amphetamine) and the inverse agonists. Both do more or less equally increase concentrations of the transmitters, but the former lead to a slowed down firing rate while the latter speed it up. This would explain the subjective differences between MPH and d-AMP, for example. For me, the phenidates are much more cognitively enhancing than the amphetamines- might be coincidence, but thinking of this it makes sense.

 

[serotonin2A]

^If cocaine and methylphenidate act as inverse agonists then it wouldn't matter if they induce autoreceptor activation -- transmitter leakage through DAT and NET wouldn't be impulse-dependent. Any drug that increases the synaptic concentration of dopamine and norepinephrine is going to increase autoreceptor activation, which will reduce the firing rate and amount of transmitter released per impulse.

Both amphetamine and cocaine are known to inhibit the firing of dopamine neurons through effects on autoreceptors, although that action may be offset by some of their other effects (ie, there may be a net increase in firing even if autoreceptor activation is very high).

 

[Nagelfar]

OK Amfonelic acid

Isn't that a straight-up DRI? (Not SNDRI?)

 

[roi]

Something doesn't have to be identical with cocaine to be just as good (which is highly subjective anyway).

 

[Nagelfar]

Something doesn't have to be identical with cocaine to be just as good (which is highly subjective anyway).

I'm not asking for something *good* (no way to know in these terms unless there is a lot of colloquial experimentation and consensus), I'm asking a pretty broad but interesting question about pharmacokinetics (or pharmaCOCAnetics, if you please), interesting because the terms are so board that not being able to find one seems unusual in & of itself.

I don't mind the thread going on to other related segues from the topic / the issue in my OP @ top, putative MAT "inverse agonism" of the compound for example, but please don't take replies to me with anything other than the face value for what I am asking: its nothing more or less than what it is; but for instance I found this interesting:

"...Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors..."

^Makes me think of my electron-energy resonance theory and cocaine's affect on the Nav sodium channels @ MAT

 

[farmacista]

Interesting that cocaine is stronger at NE than it is at 5-HT. Always thought that it was DA > 5-HT > NE. But when we think about the recently suggested 'inverse agonist' theory, that likely also applies to its 5-HT activity, it's a bit more difficult ...

Edit: But then also I'm not sure if we really need to closely replicate these values to get a worthwhile analogue. Probably an inverse agonist with anything of DA > 5-HT : or > NE could be nice ... ?

IC50 is the concentration require to inhibit 50% of the transport, so fewer values means higher potency, then it should be 5-HT> NE> DA...a bit surprising i thought it were DA> NE> 5-HT

 

[serotonin2A]

IC50 is the concentration require to inhibit 50% of the transport, so fewer values means higher potency, then it should be 5-HT> NE> DA...a bit surprising i thought it were DA> NE> 5-HT

Cocaine is effectively nonselective for DA, NE, and 5-HT. Most biological events happen on a log scale, so there isn't all that much difference between 160 nM and 241 nM. The effect of a drug is not doubled when the concentration increases from 100 nM to 200 nM.

PET studies have shown that cocaine users titrate their dosing so that DAT occupancy is between 60-75%. If we pick 70% occupation as an example, the concentration of cocaine in the brain would be ~570 nM. At that concentration, NET would be inhibited 78% and SERT would be inhibited 84% (based on the IC50 values given earlier).

The important question to ask is whether varying those NET and SERT occupation levels would actually alter the subjective response. I don't think 10% or maybe even 15% differences would actually matter all that much. There is evidence that NET occupation contributes to the rebound effects of cocaine, so it would make sense to look for analogs with lower potency at NET vs. DAT.

 

[clubcard]

SMILES CCN1C=C(C(O)=O)C(=O)c2ccc(Cc3ccccc3)nc12 |t:3|
IUPAC 7-Benzyl-1-ethyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid;
InChI 1S/C18H16N2O3/c1-2-20-11-15(18(22)23)16(21)14-9-8-13(19-17(14)20)10-12-6-4-3-5-7-12/h3-9,1...
InChI key WHHHJDGNBVQNAU-UHFFFAOYSA-N

SLC6A3 (HUMAN) (Ki 3.7 nM)

 

[dopamimetic]

There is evidence that NET occupation contributes to the rebound effects of cocaine, so it would make sense to look for analogs with lower potency at NET vs. DAT.

Based on my experiences with various stimulants, I would strongly agree to this. A bit of NE is required for the euphoric push, but it is also one of the main origins of acute rebound - isopropylphenidate being very selective for DA has little rebound and this can be completely avoided by taking the antioxidant emoxypine together with it - without dampening the effects! Have yet to find a similar acting compound for NE or 5-HT. But 5-HT depletion is probably more a thing of continued dosing and doesn't happen acutely unless one takes a strong releaser like MDMA. Also, oversimplification or not, I definitely associate too much NE with heavy anxiety and body jitteriness. Taking clonidine with stimulants takes a bit of their effects but it doesn't completely cancel them out, and there are much less after effects. And no more insomnia.

 

[Nagelfar]

SMILES CCN1C=C(C(O)=O)C(=O)c2ccc(Cc3ccccc3)nc12 |t:3|
IUPAC 7-Benzyl-1-ethyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid;
InChI 1S/C18H16N2O3/c1-2-20-11-15(18(22)23)16(21)14-9-8-13(19-17(14)20)10-12-6-4-3-5-7-12/h3-9,1...
InChI key WHHHJDGNBVQNAU-UHFFFAOYSA-N

SLC6A3 (HUMAN) (Ki 3.7 nM)

Yes, but what does this have to do with my question?

...Despite lack of direct serotonin activity, rats treated with subchronic doses of amfonelic acid display subsequent decreases in 5HT and 5HIAA. Amfonelic acid displays no activity in the norepinephrine system....