activity of UWA-101 and psychoactivity

[bloodshed344]

This is UWA-101, it is MDMA with the alpha methyl replaced with a cyclopropyl group. Papers on it say it lacks psychoactivity, common sense says otherwise. Also the numbers for its affinity to receptors says otherwise too. What are you guy's opinions?

I did make a thread about this in other drugs forum, but it received no attention and since this chemical is relatively unknown I figured that was the wrong place.

 

[ebola?]

Papers on it say it lacks psychoactivity, common sense says otherwise.

Why would common sense suggest retention of activity with ring-substitution on the alpha-chain?

ebola

 

[bloodshed344]

Why would common sense suggest retention of activity with ring-substitution on the alpha-chain?

ebola

Because of the ki values (I think it was ki values) that I saw for it. It's a much stronger releaser of dopamine and serotonin than MDMA, and much weaker releaser of Norepinephrine. Lack of the norepinephrine would definitely suggest that it's not going to be as stimulating but I highly doubt it's not psychoactive at all, rather that seems a lame attempt to somehow make it more valid to be used as a medication than MDMA. I'm sure it is much less psychoactive in effective doses, but I highly doubt that it isn't psychoactive.

Rather than a quip, would you happen to have some reason why this wouldn't be psychoactive? Recall that mescaline is psychoactive, if you take an extremely large amount (250+ mg). I don't see how this couldn't be.

 

[ebola?]

Actually, established Ki values supersede all prior discussion (though it could function primarily as a reuptake inhibitor rather than a releaser, as occurs with extension of the alpha-chain).

ebola

 

[alovesupreme]

i believe Shulgin himself remarked that putting large functional groups at that position render the compounds basically non-psychoactive and with that rule in mind i'd always assumed this would have little psychoactive potential. there is also a paper out, "A Novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances l-DOPA benefit in parkinsonian primates" (Johnston and Miller, et al, 2012) which noted that "treatment with UWA-101 did not elicit any effects consistent with psychoactivity" (at least, when compared to MDMA). of course laboratory primates can't elucidate the finer points of a chemical - their measures of psychoactivity are in that sense a bit crude - and maybe there might be something very mild in a high enough dose (i believe they tried 1 mg/kg and 3 mg/kg), but this paper seems pretty conclusive... it also advances the hypothesis, as ebola mentions, that it functions mostly as a serotonin and dopamine reuptake inhibitor.

 

[bloodshed344]

i believe Shulgin himself remarked that putting large functional groups at that position render the compounds basically non-psychoactive and with that rule in mind i'd always assumed this would have little psychoactive potential. there is also a paper out, "A Novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances l-DOPA benefit in parkinsonian primates" (Johnston and Miller, et al, 2012) which noted that "treatment with UWA-101 did not elicit any effects consistent with psychoactivity" (at least, when compared to MDMA). of course laboratory primates can't elucidate the finer points of a chemical - their measures of psychoactivity are in that sense a bit crude - and maybe there might be something very mild in a high enough dose (i believe they tried 1 mg/kg and 3 mg/kg), but this paper seems pretty conclusive... it also advances the hypothesis, as ebola mentions, that it functions mostly as a serotonin and dopamine reuptake inhibitor.

Actually I know of that paper and thought I linked it in the original post but I guess not. I think that paper is possibly wrong in that regard. The ki numbers say differently at least.

 

[electrodevo]

it also advances the hypothesis, as ebola mentions, that it functions mostly as a serotonin and dopamine reuptake inhibitor.

I get via a Wiki that this is also a serotonin / dopamine releasing agent as well (no numbers though). This compound thus has a unique profile, apparently it's the only serotonin / dopamine releaser out there that doesn't touch norepinephrine. The problem with the "activity" of UWA-101 that I can see right off the bat is that it does not have much affinity for 5-HT2A.

I'm not sure if there is a direct relationship between Ki or IC50 values and actual psychoactivity, either (although sometimes that gives a clue, I guess sometimes it doesn't). The paper mentions another compound, UWA-001 (2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-phenylethanamine), which has strong affinity for 5HT2A, SERT, and NET (insignificant affinity for DAT though). It is said to be "non-psychedelic" though. Hmm.

 

[bloodshed344]

I get via a Wiki that this is also a serotonin / dopamine releasing agent as well (no numbers though). This compound thus has a unique profile, apparently it's the only serotonin / dopamine releaser out there that doesn't touch norepinephrine. The problem with the "activity" of UWA-101 that I can see right off the bat is that it does not have much affinity for 5-HT2A.

I'm not sure if there is a direct relationship between Ki or IC50 values and actual psychoactivity, either (although sometimes that gives a clue, I guess sometimes it doesn't). The paper mentions another compound, UWA-001 (2-(benzo[d][1,3]dioxol-5-yl)-N-methyl-1-phenylethanamine), which has strong affinity for 5HT2A, SERT, and NET (insignificant affinity for DAT though). It is said to be "non-psychedelic" though. Hmm.

I thought dopamine/serotonin releasers/reuptake inhibitors were by definition psychoactive unless there is some other mechanism that overshadows these two effects.

 

[endotropic]

I thought dopamine/serotonin releasers/reuptake inhibitors were by definition psychoactive unless there is some other mechanism that overshadows these two effects.

There could be absorption or distribution problems. I don't see how substituting one non-polar group for another would make that much of a difference, but the BBB can be a fickle creature.

 

[bloodshed344]

There could be absorption or distribution problems. I don't see how substituting one non-polar group for another would make that much of a difference, but the BBB can be a fickle creature.

Well, no, that wouldn't explain it because it obviously works to treat whatever condition it was for again. Unless it does act peripherally and that is how it helps?

 

[specialspack]

Because of the ki values (I think it was ki values) that I saw for it. It's a much stronger releaser of dopamine and serotonin than MDMA, and much weaker releaser of Norepinephrine.

The ki values only tell you about affinity at the transporter, they don't tell you anything about whether the compound is a releaser or not. Especially since the mechanism of MDMA release is probably to do more with VMAT, pushing the intracellular concentration of 5HT to the level that drives SERT to function in reverse.

 

[electrodevo]

I thought dopamine/serotonin releasers/reuptake inhibitors were by definition psychoactive unless there is some other mechanism that overshadows these two effects.

Psychoactive in what way, I guess, is the question. MDMA is not like many stimulants in that it is also agonizes 5HT1A and 5HT2A, the later being the receptor of classic psychedelics, the former speculated to increase oxytocin release. I think that might be in part what makes MDMA a special recreational compound.

Still, even without 5HT agonism, I would guess that UWA-101 would be a stimulant of some sort at some dose -- you'd think anything with strong affinity for DAT would be (maybe without NE, it would be quite different of course, but I don't know how). The question is, in what way (as I don't believe Ki/IC50 tells you the mechanism of action)?

To take one example, the antidepressant bupropion has *very* strong NE/DAT IC50 values. Yet as a recreational stimulant, it's reportedly very shitty.

 

[Limpet_Chicken]

I'd be concerned about potential MAOI(a) activity.

Phenylcyclopropanamines often do have MAO(a) inhibitor activity, irreversibly, tranylcypromine being the most well known

http://en.wikipedia.org/wiki/Tranylcypromine (I'd include the structure, but ATM I have no way to right-click anything, my mouse is out of action)

Granted this compound has the cyclopropyl as an alpha substituent rather than incorporated into the chain directly, but it is a little too close for comfort in a possible monoamine releaser.

 

[bloodshed344]

I'd be concerned about potential MAOI(a) activity.

Phenylcyclopropanamines often do have MAO(a) inhibitor activity, irreversibly, tranylcypromine being the most well known

http://en.wikipedia.org/wiki/Tranylcypromine (I'd include the structure, but ATM I have no way to right-click anything, my mouse is out of action)

Granted this compound has the cyclopropyl as an alpha substituent rather than incorporated into the chain directly, but it is a little too close for comfort in a possible monoamine releaser.

Sounds fun.

 

[sekio]

Why would you expect this compound to be a MAO-I, when compounds like e.g. phentermine and MDPH are not? (even compounds like e.g. MDPV, butylone)

Just because there's a cyclopropyl ring does not make it some sort of magical MAO inhibitor.

 

[Limpet_Chicken]

I did not make that claim. I simply drew attention to the structural similarity. Since this compound is not well known, it is worth bearing in mind the possibility it MAY possess such activity. So people can work with it with appropriate caution.