Listen - things that actually BIND to the dopamine receptors are for treating Parkinson's disease & such - as others have pointed out. Cocaine works by altering transport. SLC63A is the protein amfonelic acid binds to, to increase MA transport. The values you assign (the Ki values) are LOW. So find the protein cocaine works on. And LogP and pKa are BOTH VERY IMPORTANT in the action of a drug. GIGO.
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N&PD Moderators: Skorpio | thegreenhand
A truly, equal across the board, SNDRI to rival cocaine?
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SKL
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I once "autobioassayed" β-CFT (WIN 35,428)
it was pretty neat, although not rivaling cocaine per se, some interesting notes in that thread though fwiw ....
it was pretty neat, although not rivaling cocaine per se, some interesting notes in that thread though fwiw ....
serotonin2A
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I'm a little confused by what you mean here. SLC6A3 is the gene that encodes the dopamine transporter. DAT is the protein that cocaine and amfonelic acid work on.
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All i gotta say is OMG you all have done your research, I will try to do the same and try to leave some input myself. very interesting article even though i dont think cocaine is beneficial in any way possible but i wont judge until i dig the right facts up. +1 for creativity.
aced126
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Cocaine works on DAT as well. The values assigned make sense; amnofelic acid seems potent. According to wiki it is x50 methylphenidate, so those low values are expected. LogP and pKa are obviously important but not really in in vitro testing, which is what this is essentially about.
Saw that WIN 35,428 along with RTI-55 in my old Pharmacology book. Lead me to this page:
https://en.wikipedia.org/wiki/(+)-CPCA
The thought of insufflating halogenated analogs makes my nose hurt just thinking about dumb experiences with 2C-B
https://en.wikipedia.org/wiki/(+)-CPCA
The thought of insufflating halogenated analogs makes my nose hurt just thinking about dumb experiences with 2C-B
Nagelfar
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When the 'cocaine receptor' is mentioned it's construed as the binding site on DAT, and not the DA receptors, is this what you're getting at? cc all of your responses make little to no sense in the context of what I am asking in this thread. Did you see my question I newly added to your "cocaine replacement" thread?
What do you mean "beneficial"? In terms of being the most acutely addictive drug, natural or otherwise, out of all researched patterns of human habituation with chemicals I'd say its a very *interesting* compound. The latter is due to the pharmacokinetics of its rapid onset and ability to bind to its target with such a rapid metabolic lability; much of which aren't pointed to in the literature in as stark a contrast with other drugs as it should be IMHO.
SKL
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Saw that WIN 35,428 along with RTI-55 in my old Pharmacology book. Lead me to this page:
https://en.wikipedia.org/wiki/(+)-CPCA
The thought of insufflating halogenated analogs makes my nose hurt just thinking about dumb experiences with 2C-B
i iv'd it. also tried RTI-121 which was underwhelmng.
WIN 35,428 while not specifically a cocaine "rival" in terms of exact subjective profile has a lot of potential
by no means an easy synth though
considering cocaine is more than simply a transporter inhibitor, then binding values wouldn't predict how similar to cocaine a given drug would be, i guess. we'd need something like efficacy at triggering whatever cocaine does to the transporters, right?
like PAL-287, which has a high affinity for all the monoamine transporters but fails to evoke release and sucks as a drug, if i'm not mistaken.
like PAL-287, which has a high affinity for all the monoamine transporters but fails to evoke release and sucks as a drug, if i'm not mistaken.
Nagelfar
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I figured that iometopane, RTI-31 & RTI-32 would be better than the para-fluoro due to affinities. Again, the reason for starting this thread is *not* looking for a "rival" of cocaine, just...
...just looking for one one that inhibits uptake (which is what it *does*, in this sense) of the three MAT types in an as equal or more equal discrimination between the three than/as cocaine itself. Which are the values I'm looking at, not the binding / displacement values of ligands for the site of binding, but the inhibition of re-uptake for the neurotransmitters themselves, and that *is* the values I gave in the original post.
For example: the displacement value for cocaine @ DA re-uptake is, as I gave above: 241 ± 18
but for *binding* to DAT (displacing labeled WIN 35,428 ) it's: 102 ± 12
inhibiting serotonin: 112 ± 2
but for *binding* to SERT (displacing labeled paroxetine) its: 1045 ± 89
norepinephrine re-uptake is: 160 ± 15
however binding to the NET site that allows it to inhibit said re-uptake (displacing labeled nisoxetine) is: 3298 ± 293
This means that cocaine's affinity for the target binding site, using certain staple compounds as a measure against, it's:
DAT>(by a measure of ten fold)SERT>(three point two fold to SERT, thirty two to DAT)NET
yet looking at once bound, how well it inhibits the re-uptake of each one it is:
5HT>(about a third more)NE>DA(about half the value of for 5HT)
So target binding for cocaine is
DAT>SERT>NET
...which may or may not play a role with putative "inverse agonism" of each
but the actual inhibition follows the below scheme:
5HT>NE>DA
(serotonin>norepinephrine>dopamine)
so dopamine jumps from first to last, and SERT/5HT stays ahead of NE in both manners of quantifying cocaine's efficacy.
a)Read wiki again - dose 50mg
b)LogP & pKa are as VITAL as the A in the ADME cycle.
c)read Lipinski's 'rules of 5'
aced126
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Direct quote from Wikipedia's page on Amfonelic acid: "A study found a moderately long half-life of approximately 12 hours and a dopaminergic potency approximately 50 fold that of methylphenidate in rat brain preparations."
Source: https://www.ncbi.nlm.nih.gov/pubmed/2145054
In the abstract it quotes: "Cocaine, GBR 12909, amfonelic acid, and methylphenidate each biphasically inhibited uptake in the striatum, nucleus accumbens and olfactory tubercle with GBR 12909 and amfonelic acid being approximately 50-fold more potent than cocaine or methylphenidate."
They are testing in vitro pharmacodynamic properties. I agree logP and pKa values play a crucial role in pharmacokinetic properties, but this drug is nowhere close to reaching the point where these kinds of properties are going to be assessed. First, it should have a useful pharmacodynamic profile, which pKa and (to a lesser extent) logP play much less significant roles in than the actual structure of the molecule.
Lipinski's rule of five is a rule of thumb and there are so many drugs which break many of the rules. Ironically the world's best selling drug fails to comply with the rule of five. Also, all 3 molecules in question, cocaine, ritalin and amfonelic acid, all satisfy Lipinski's rule of five.
serotonin2A
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The last two factors wouldn't apply because the OP was asking about in vitro potency.
In any event, Lipinsky's rule probably isn't a huge consideration here because cocaine analogs are seldom used orally.
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aced126
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Although admittedly if analogues were ever created that could be used medicinally or recreationally (controlled, like alcohol), oral consumption would likely be the ROA and then these kinds of properties would need to be considered carefully. But until that stage, they are of insignificance.
Errrrr..... wrong
SKL
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simplifying the molecule a little bit is rewarding
but IME awarding precisely because of the differences in affinity ratios
decreasing Na channel blocking is a big plus in those compounds too
also
lol at the fact that this is basically my facial expression looking at that post
but IME awarding precisely because of the differences in affinity ratios
decreasing Na channel blocking is a big plus in those compounds too
also
lol at the fact that this is basically my facial expression looking at that post
serotonin2A
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Can you please explain how those factors would effect the action of ligands at the dopamine transporter in vitro? Even though you wrote "wrong", that doesn't give any actual evidence.
Does having roughly equal effects on all monoamine transporter sites make something more euphoric or addictive than, say, a selective DRI? Because I'm fairly sure amfonelic acid is a very selective (and quite potent) DRI, but doesn't appear to have anywhere near the same addiction potential. DRIs are a strange beast for me. The classic ones like Ritalin (never tried coke) tend to make me anxious, dysphoric, and cause cognitive problems - as do the few DRAs/amphetamine-type drugs I've tried - yet armodafinil (a supposedly weak and seemingly selective DRI) lifts my mood considerably and gives me a ton of useful energy. I'm more of a downer person in general, but this has always intrigued me.
Nagelfar
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Is it the opinion of those learned about chemistry on the board that displacement of ligand binding takes priority over inhibition of DA in measurement in potential overall efficacy? I'd assume if a compound had amazing inhibition of re-uptake, but low ligand displacement, it doesn't associate to the target site as well without readily disassociating and therefore not showing a presence; it'd be lower in its overall efficacy because it doesn't bind to the site relatively as well, even if: though when bound, it does it's job exceptionally...
...or is it the general consensus that the inhibition of a particular third party ligand or another in vitro does not necessary bode for how the compound in question binds when not in the presence of another ligand needing to be displaced and it's mostly a matter of actual neurotransmitter inhibition that shows the efficacy (e.g. the displacement of other compounds in contrast to inhibition of uptake is mostly a concern of looking at it from an angle of antagonism specifically). Which takes more precedence, for the most part, for the efficacy of a compound?
There's some intriguing dynamics of the Na action potential damming because there is sodium dependent transport sites that are distinct & specific to MAT (besides the pervasive sodium channels that give the topical anesthetic effect)
...or is it the general consensus that the inhibition of a particular third party ligand or another in vitro does not necessary bode for how the compound in question binds when not in the presence of another ligand needing to be displaced and it's mostly a matter of actual neurotransmitter inhibition that shows the efficacy (e.g. the displacement of other compounds in contrast to inhibition of uptake is mostly a concern of looking at it from an angle of antagonism specifically). Which takes more precedence, for the most part, for the efficacy of a compound?
There's some intriguing dynamics of the Na action potential damming because there is sodium dependent transport sites that are distinct & specific to MAT (besides the pervasive sodium channels that give the topical anesthetic effect)
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serotonin2A
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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.