resorcinol
03-23-2009, 08:21 PM
.. stuff too) ----
This one caught my eye because it's possibly the only drug with confirmed psychoactivity of the recreational type that has a selenium atom in its structure:
http://upload.wikimedia.org/wikipedia/commons/thumb/1/1e/2C-SE.svg/200px-2C-SE.svg.png
That's 2C-Se (2,5-methoxy-4-methylselenophenylethylamine). In the Pikhal data, 70 mg gave mild effects. I gathered that Shulgin was concerned with POSSIBLE toxicity of organic compounds that have structures similar to essential amino acids (in the case, as with all phenethylamines, the essential amino acid parent is phenylalanine) and have Selenium heteroatoms in them. POTENTIAL toxicity though: Shulgin had heard of some organoselenium compounds that had higher toxicity than their analogs with other heteroatoms and was mildly worried. This is nothing like the psychoactive CB1 agonists with NO heteroatoms though (plain polycyclic aromatic hydrocarbons) with are almost certainly toxic to some degree since the only metabolic pathway is aromatic epoxidation, and those metabolites are DNA intercalators I believe which can cause harmful mutations) -- IMO the toxicity concern with these organoselenium psychoactives is almost certainly far lower (low enough that shulgin and his other tester friends in Pihkal were willing to try a little of 2C-Se).
At 70 mg, psychedelic effects were noted, but were mild. Shulgin seemed to believe that ramping the dosage up to 100 mg would result in a solid trip: so 2C-Se was a success compared to, say, 2C-N which was a flop, yet we hear little of 2C-Se. It's one of the overlooked drugs in Pihkal, maybe simply because of Shulgin's comment about POSSIBLE toxicity, or just because the synth is more difficult than for other Pihkal substances (I don't know whether that's true: I have very little lab experience, only intermediate conceptual understanding of organic reactions). Shulgin also seemed to think that 2C-Se-21, the selenium analog of the sulfur containing 2C-T-21. I personally think the amphetamine analog would also be interesting (Shulgin didn't mention this compound, though).
The amphetamine analogs of all of the other 2C drugs seem to be more potent (however, some RC psychonauts seem to feel that the amphetamine analogs of 2C series psychedelics are also "dirtier" due to a body load higher than the parent compound without the alpha methyl group. Also, correct me if I'm wrong, but don't the amphetamine analogs of phenethylamine psychedelics typically have a longer T-1/2 for elimination than the unsubstituted parent? That may be undesirable for many folks). It follows though, that DOSe (2,5-methoxy-4-methylselenoamphetamine), would be more potent than 2C-Se, should the SAR for the rest of the class hold up. Due to 2C-Se by itself not having extreme potency compared to 2C-I and the other halogenated 2C drugs (except 2C-F, which is quite weak, probably because the atomic radius of fluorine is too small to fit nicely into the pocket in the 5HT(2a) receptor that accommodates the necessary 4 substituent for this class -- the unsubstituted 2C-H is essentially inactive... well it might be WEAKLY active, but MAO attacks it so readily that we would not be able to ascertain even weak affinity for the psychedelic receptor in vivo. DOF, though, is predicted to be active in the dose range of 6 to 18 mg, or approx 12 mg -- while 2C-F produces only threshold effects at 250 mg) DOSe is a candidate for having a desirable potency -- not too strong that dosing is difficult, but not so weak that the amounts of powder are a pain to work with and that side effects might become more prominent.
I also know the DOx drugs produce some tweaky feelings for some people, possibly due to some amphetaminergic monoamine release, but IMO at their dosages the 5HT(2a) agonism should overwhelm the amphetaminergic effects.
Even plain 2C-Se though is more potent than mescaline as a classical psychedelic based on the Pihkal data. If low toxicity could be VERIFIED somehow, I think it could be an interesting research chemical to try, and a door opener for other organoselenium drugs.
Now the REALLY good part: I see POTENTIAL for organoselenium opioids. Imagine oxycodone, but ditch the methoxy group on position 3 and replace it with a methylseleno group: a direct analog using a different chalcogen heteroatom (selenium instead of oxygen). It's probably active -- the prime question is: does having a Se there instead of an O have SAR such that they methyl group on the chalcogen atom results in MORE or LESS decrease in potency. The second prime question is: Does a methylseleno group confer the same very high resistence to first pass metabolism (hence great bioavailability) that having a methoxy group there does? The third prime question is: would this opioid have acceptably low toxicity? (I'm betting on YES, but it's ALWAYS a worry when dealing with "research chemicals" / "designer drugs", ESPECIALLY when introducing a new heteroatom -- but my gut tells me it would not be toxic. My gut isn't enough for me or anyone else to feel safe to have a blast though. See, if prohibition was ended, these new designer drugs could undergo rigorous safety testing and we'd know for sure. Honestly even playing with any of the 2C compounds is taking a risk to a degree as we really don't know much about them besides their agonism of 5HT(2a) and their half-lives (how much we know varies from designer phenethylamine to phenethylamine; we know more about 2C-B than, say, 2C-T-x ... any of those)).
Flip it around now (back to opioids and selenium). How about a methylseleno group at position 6 on DIHYDROMORPHINE instead of the hydroxyl group? Judging from the potency of heterocodeine (6-methylmorphine), this selenium heteroatom containing drug would be potent. It would be 6-methylseleno-desoxydihydromorphine.
Shifting gears again: another rare 2C psychedelic:
http://upload.wikimedia.org/wikipedia/en/thumb/2/2b/2C-TFM.png/180px-2C-TFM.png
2C-TFM (2,5-methoxy-4-trifluoromethanephenethylamine)
2C-TFM, unline 2C-Se, is quite potent indeed: 3 to 5 mg is reportedly a solidly active dosage. There's a simple reason why this seemingly random substituent group produces such a potent 5HT(2a) agonist psychedelic: The trifluoromethyl group is a "pseudohalogen". That means that TFM groups behave like a single halogen heteroatom does as a substutuent due to having a very similar electrical charge density around the group and its bonds as just a halogen and its bond and also having a functional group radii similar to the radius of the lager halogens. In addition their chemical behavior is very similar to that of a true halogen atom. Judging by potency of 2C-TFM, the radius of the whole TFM group is actually probably larger than the radius of iodine, because 2C-TFM appears to be more potent than 2C-I. This is of interest because it's the closest we'll likely ever get to knowing what 2C-At would feel like if Astatine wasn't radioactive (even the most stable isotopes are so fantastically radioactive with short nuclear T-1/2 values that a visible quantity of At or an At compound would decay before you could even catch a decent glimpse ... and you'd hit the ground cold dead shortly after catching that glimpse from massive acute radiation poisoning).
One final comment about organoselenium opioids: what about 14-methylseleno-hydrocodone? Bet that one would rock our world.
If we could verify that organoselenium compounds aren't particularly toxic except for a few baddies, it really would open the door for some new drugs. I think the toxicity concern is LESS with the hypothetical opioids than with the phenethylamine Se drugs since the phenethylamine Se drugs are analogs of phenylalanine, an essential amino acid, and the phenanthrene / morphine like opioids, structurally, are not amino acids nor do they resemble any biological amino acid.
On phenylalanine: it's really actually the reason that phenylethylamines are psychoactive (well, a lot of them are, plenty are inactive too). I mean, it's the reason why that backbone is so pervasive in psychoanaleptic recreational drugs (those that augment excitatory neurotransmission): the phenylalanine we eat is used to biosynthesize the monoamine neurotransmitters (except for serotonin, for which tryptophan is the amino acid precursor). Phenylalanine is the bio-precursor for dopamine, norepinephrine, and epinephrine.
Oddly, the phenylethylamine backbone is present (can be traced out) in morphine-like opioids (although since that backbone is so massively substituted the pharmacology is hugely changed and the Selenium-amino acid analog worries would not apply).
The aromatic ring with a two carbon spacer between it and an amine group is fucking PERVASIVE in recreational drugs. Morphine like opioids and phenethylamines BOTH have this feature. It's interesting to speculate as to why this feature is so hot for producing psychoactive substances.
This one caught my eye because it's possibly the only drug with confirmed psychoactivity of the recreational type that has a selenium atom in its structure:
http://upload.wikimedia.org/wikipedia/commons/thumb/1/1e/2C-SE.svg/200px-2C-SE.svg.png
That's 2C-Se (2,5-methoxy-4-methylselenophenylethylamine). In the Pikhal data, 70 mg gave mild effects. I gathered that Shulgin was concerned with POSSIBLE toxicity of organic compounds that have structures similar to essential amino acids (in the case, as with all phenethylamines, the essential amino acid parent is phenylalanine) and have Selenium heteroatoms in them. POTENTIAL toxicity though: Shulgin had heard of some organoselenium compounds that had higher toxicity than their analogs with other heteroatoms and was mildly worried. This is nothing like the psychoactive CB1 agonists with NO heteroatoms though (plain polycyclic aromatic hydrocarbons) with are almost certainly toxic to some degree since the only metabolic pathway is aromatic epoxidation, and those metabolites are DNA intercalators I believe which can cause harmful mutations) -- IMO the toxicity concern with these organoselenium psychoactives is almost certainly far lower (low enough that shulgin and his other tester friends in Pihkal were willing to try a little of 2C-Se).
At 70 mg, psychedelic effects were noted, but were mild. Shulgin seemed to believe that ramping the dosage up to 100 mg would result in a solid trip: so 2C-Se was a success compared to, say, 2C-N which was a flop, yet we hear little of 2C-Se. It's one of the overlooked drugs in Pihkal, maybe simply because of Shulgin's comment about POSSIBLE toxicity, or just because the synth is more difficult than for other Pihkal substances (I don't know whether that's true: I have very little lab experience, only intermediate conceptual understanding of organic reactions). Shulgin also seemed to think that 2C-Se-21, the selenium analog of the sulfur containing 2C-T-21. I personally think the amphetamine analog would also be interesting (Shulgin didn't mention this compound, though).
The amphetamine analogs of all of the other 2C drugs seem to be more potent (however, some RC psychonauts seem to feel that the amphetamine analogs of 2C series psychedelics are also "dirtier" due to a body load higher than the parent compound without the alpha methyl group. Also, correct me if I'm wrong, but don't the amphetamine analogs of phenethylamine psychedelics typically have a longer T-1/2 for elimination than the unsubstituted parent? That may be undesirable for many folks). It follows though, that DOSe (2,5-methoxy-4-methylselenoamphetamine), would be more potent than 2C-Se, should the SAR for the rest of the class hold up. Due to 2C-Se by itself not having extreme potency compared to 2C-I and the other halogenated 2C drugs (except 2C-F, which is quite weak, probably because the atomic radius of fluorine is too small to fit nicely into the pocket in the 5HT(2a) receptor that accommodates the necessary 4 substituent for this class -- the unsubstituted 2C-H is essentially inactive... well it might be WEAKLY active, but MAO attacks it so readily that we would not be able to ascertain even weak affinity for the psychedelic receptor in vivo. DOF, though, is predicted to be active in the dose range of 6 to 18 mg, or approx 12 mg -- while 2C-F produces only threshold effects at 250 mg) DOSe is a candidate for having a desirable potency -- not too strong that dosing is difficult, but not so weak that the amounts of powder are a pain to work with and that side effects might become more prominent.
I also know the DOx drugs produce some tweaky feelings for some people, possibly due to some amphetaminergic monoamine release, but IMO at their dosages the 5HT(2a) agonism should overwhelm the amphetaminergic effects.
Even plain 2C-Se though is more potent than mescaline as a classical psychedelic based on the Pihkal data. If low toxicity could be VERIFIED somehow, I think it could be an interesting research chemical to try, and a door opener for other organoselenium drugs.
Now the REALLY good part: I see POTENTIAL for organoselenium opioids. Imagine oxycodone, but ditch the methoxy group on position 3 and replace it with a methylseleno group: a direct analog using a different chalcogen heteroatom (selenium instead of oxygen). It's probably active -- the prime question is: does having a Se there instead of an O have SAR such that they methyl group on the chalcogen atom results in MORE or LESS decrease in potency. The second prime question is: Does a methylseleno group confer the same very high resistence to first pass metabolism (hence great bioavailability) that having a methoxy group there does? The third prime question is: would this opioid have acceptably low toxicity? (I'm betting on YES, but it's ALWAYS a worry when dealing with "research chemicals" / "designer drugs", ESPECIALLY when introducing a new heteroatom -- but my gut tells me it would not be toxic. My gut isn't enough for me or anyone else to feel safe to have a blast though. See, if prohibition was ended, these new designer drugs could undergo rigorous safety testing and we'd know for sure. Honestly even playing with any of the 2C compounds is taking a risk to a degree as we really don't know much about them besides their agonism of 5HT(2a) and their half-lives (how much we know varies from designer phenethylamine to phenethylamine; we know more about 2C-B than, say, 2C-T-x ... any of those)).
Flip it around now (back to opioids and selenium). How about a methylseleno group at position 6 on DIHYDROMORPHINE instead of the hydroxyl group? Judging from the potency of heterocodeine (6-methylmorphine), this selenium heteroatom containing drug would be potent. It would be 6-methylseleno-desoxydihydromorphine.
Shifting gears again: another rare 2C psychedelic:
http://upload.wikimedia.org/wikipedia/en/thumb/2/2b/2C-TFM.png/180px-2C-TFM.png
2C-TFM (2,5-methoxy-4-trifluoromethanephenethylamine)
2C-TFM, unline 2C-Se, is quite potent indeed: 3 to 5 mg is reportedly a solidly active dosage. There's a simple reason why this seemingly random substituent group produces such a potent 5HT(2a) agonist psychedelic: The trifluoromethyl group is a "pseudohalogen". That means that TFM groups behave like a single halogen heteroatom does as a substutuent due to having a very similar electrical charge density around the group and its bonds as just a halogen and its bond and also having a functional group radii similar to the radius of the lager halogens. In addition their chemical behavior is very similar to that of a true halogen atom. Judging by potency of 2C-TFM, the radius of the whole TFM group is actually probably larger than the radius of iodine, because 2C-TFM appears to be more potent than 2C-I. This is of interest because it's the closest we'll likely ever get to knowing what 2C-At would feel like if Astatine wasn't radioactive (even the most stable isotopes are so fantastically radioactive with short nuclear T-1/2 values that a visible quantity of At or an At compound would decay before you could even catch a decent glimpse ... and you'd hit the ground cold dead shortly after catching that glimpse from massive acute radiation poisoning).
One final comment about organoselenium opioids: what about 14-methylseleno-hydrocodone? Bet that one would rock our world.
If we could verify that organoselenium compounds aren't particularly toxic except for a few baddies, it really would open the door for some new drugs. I think the toxicity concern is LESS with the hypothetical opioids than with the phenethylamine Se drugs since the phenethylamine Se drugs are analogs of phenylalanine, an essential amino acid, and the phenanthrene / morphine like opioids, structurally, are not amino acids nor do they resemble any biological amino acid.
On phenylalanine: it's really actually the reason that phenylethylamines are psychoactive (well, a lot of them are, plenty are inactive too). I mean, it's the reason why that backbone is so pervasive in psychoanaleptic recreational drugs (those that augment excitatory neurotransmission): the phenylalanine we eat is used to biosynthesize the monoamine neurotransmitters (except for serotonin, for which tryptophan is the amino acid precursor). Phenylalanine is the bio-precursor for dopamine, norepinephrine, and epinephrine.
Oddly, the phenylethylamine backbone is present (can be traced out) in morphine-like opioids (although since that backbone is so massively substituted the pharmacology is hugely changed and the Selenium-amino acid analog worries would not apply).
The aromatic ring with a two carbon spacer between it and an amine group is fucking PERVASIVE in recreational drugs. Morphine like opioids and phenethylamines BOTH have this feature. It's interesting to speculate as to why this feature is so hot for producing psychoactive substances.