resorcinol
08-26-2009, 08:35 PM
... structures?
I can think of a few off the top of my head.
My favorite is....
Lefetamine:
http://upload.wikimedia.org/wikipedia/commons/thumb/4/4b/Lefetamine.svg/130px-Lefetamine.svg.png
Lefetamine is really a substituted phenethylamine. It's SIMILAR in structure to amphetamines, but has a phenyl group at the alpha carbon rather than a methyl group (Alpha Methyl PHenyl EThyl AMINE is actually how amphetamine was "named"). It's still very simple ... the amine of PEA is dimethylated, and the alpha carbon has a phenyl ring stuck on it ... those are the two changes to the PEA backbone to result in lefetamine. The folks who made it surely only expected to get a psychostimulant of the amphetamine type, and were probably quite shocked at the respectable opioid mu agonist activity. I'm not certain of the exact potency, but I believe it's between half the potency of to the same potency as morphine. This isn't potent in the grander scheme of opioids, but is remarkable for such a simple molecule. It's even more remarkable for another reason ... lefetamine IS a stimulant, but a DNRI (not a DA & NE releaser like dexamphetamine) of about the same potency as racemic methylphenidate (which is respectably potent).
There's the WOW, fuckin' cool, factor. It's got respectable potency as both a mu opioid agonist and as a DNRI psychostimulant. I'd guess it has phenomenally high recreational potential (and thus doesn't have a chance in hell of being marketed for chronic pain ... then again, it could benefit CP patients who are very sensitive to and intolerant of the sedation caused by opioids ... instead of adding a stim drug, they could switch to lefetamine which is an opioid and a psychostimulant in one drug / compound). Its DNRI effects are said to be very very alike methylphenidate's (not surprising since its structure is similar to MPH ... they're both sorta like "fat" amphetamines). Looking at it, I can see how it manages to fit the mu receptor as an agonist well enough to be either half morphine's or equal to morphine's potency as an opioid ... but I'd have never guessed it before hand ... lefetamine was a lucky discovery. I can also see that probably not a thing could be modified on the lefetamine molecule w/out loosing significant potency as either a DNRI or as an opioid mu agonist. It's just a remarkable molecule. It also demonstrates how QUITE simple molecules can be mu receptor agonists even though the prototype agonist for the receptor, morphine, is a bit on the complicated side.
Tapentadol:
http://upload.wikimedia.org/wikipedia/commons/thumb/c/c9/Tapentadol.svg/220px-Tapentadol.svg.png
This, overall, isn't more impressive than lefetamine (lefetamine is a euphoric upper AND an opioid mu agonist ... how friggin more awesome could ya get from a simple molecule), but it's still impressive.
The main impressive thing? It has ONE ring and it's a mu receptor agonist. Even TRAMADOL has two rings (one aromatic, one saturated). This just has ONE aromatic ring. I feel it pulls it off via those numerous side chains. They probably look like "partial" rings to the receptors the drug binds to. The dimethylated amine at the terminal end is a common feature in simplistic opioid agonist molecules. So, yeah. Really simple opioid here. One aromatic ring, a saturated side chain off it terminating with a dimethylamine group, and a methyl side side chain at the beta carbon, and an ethyl side side chain at the gamma carbon (those two, I feel, mimic more ring presence even though they're not rings at all .... just the way they're positioned in space "fills out" the molecule if you can picture it).
The brand name of this drug, tapentadol, is Nucynta. It was released not long ago, and you can now be given a Rx for it for acute or chronic pain. It was placed in CII when clinical trials found equianalgesic doses of tapentadol and hydromorphone to be equally rated on the scales for "fun", "enjoyability", and "liking". Grunenthal knew tapentadol would be much more euphoric than tramadol which managed to get approved as a non-controlled substance, but they were angling for C-III. All hope for C-III was lost when the trial with tapentadol and hydromorphone equipotent doses showed equivalent enjoyability at equipotent doses and tapentadol was hammered into C-II with most other decent opioids. Tapentadol is not POTENT (I believe 200 mg tapentadol was equipotent to 8 mg hydromorphone, both orally) but apparently it can be pretty powerful at the right dose. I think 8 mg even oral hydromorphone would get me pretty high, so 200 mg tapentadol would probably get me pretty high also.
Some other somewhat simple ones are pethidine, ethylmethylthiambutene, ketobemidone, levorphanol, levomethorphan, and of course tramadol (but tramadol is a VERY weak opioid) ... but the above two impressed me the most (especially lefetamine).
If anyone can think of anything really simple that I missed or has any thoughts on these drugs ... shoot. I know not many folks have tried tapentadol (Nucynta) yet and that very few folks have or will ever get the chance to try lefetamine. For folks that get a chance to take Nucynta ... take a big enough dose. Use those figures from the clinical trial that landed it in C-II waters (8 mg hydromorphone equals 200 mg tapentadol, both oral) and calculate how much tapentadol you'd need to get high based on how much oral hydromorphone you'd need to get high. If you need 24 mg oral hydromorphone to get a solid strong buzz, then you'd need 600 mg tapentadol to get that same strength buzz, so it'd be unfair to take 100 mg tapentadol and proclaim "it friggin sucks, it's weak" in that situation.
I can think of a few off the top of my head.
My favorite is....
Lefetamine:
http://upload.wikimedia.org/wikipedia/commons/thumb/4/4b/Lefetamine.svg/130px-Lefetamine.svg.png
Lefetamine is really a substituted phenethylamine. It's SIMILAR in structure to amphetamines, but has a phenyl group at the alpha carbon rather than a methyl group (Alpha Methyl PHenyl EThyl AMINE is actually how amphetamine was "named"). It's still very simple ... the amine of PEA is dimethylated, and the alpha carbon has a phenyl ring stuck on it ... those are the two changes to the PEA backbone to result in lefetamine. The folks who made it surely only expected to get a psychostimulant of the amphetamine type, and were probably quite shocked at the respectable opioid mu agonist activity. I'm not certain of the exact potency, but I believe it's between half the potency of to the same potency as morphine. This isn't potent in the grander scheme of opioids, but is remarkable for such a simple molecule. It's even more remarkable for another reason ... lefetamine IS a stimulant, but a DNRI (not a DA & NE releaser like dexamphetamine) of about the same potency as racemic methylphenidate (which is respectably potent).
There's the WOW, fuckin' cool, factor. It's got respectable potency as both a mu opioid agonist and as a DNRI psychostimulant. I'd guess it has phenomenally high recreational potential (and thus doesn't have a chance in hell of being marketed for chronic pain ... then again, it could benefit CP patients who are very sensitive to and intolerant of the sedation caused by opioids ... instead of adding a stim drug, they could switch to lefetamine which is an opioid and a psychostimulant in one drug / compound). Its DNRI effects are said to be very very alike methylphenidate's (not surprising since its structure is similar to MPH ... they're both sorta like "fat" amphetamines). Looking at it, I can see how it manages to fit the mu receptor as an agonist well enough to be either half morphine's or equal to morphine's potency as an opioid ... but I'd have never guessed it before hand ... lefetamine was a lucky discovery. I can also see that probably not a thing could be modified on the lefetamine molecule w/out loosing significant potency as either a DNRI or as an opioid mu agonist. It's just a remarkable molecule. It also demonstrates how QUITE simple molecules can be mu receptor agonists even though the prototype agonist for the receptor, morphine, is a bit on the complicated side.
Tapentadol:
http://upload.wikimedia.org/wikipedia/commons/thumb/c/c9/Tapentadol.svg/220px-Tapentadol.svg.png
This, overall, isn't more impressive than lefetamine (lefetamine is a euphoric upper AND an opioid mu agonist ... how friggin more awesome could ya get from a simple molecule), but it's still impressive.
The main impressive thing? It has ONE ring and it's a mu receptor agonist. Even TRAMADOL has two rings (one aromatic, one saturated). This just has ONE aromatic ring. I feel it pulls it off via those numerous side chains. They probably look like "partial" rings to the receptors the drug binds to. The dimethylated amine at the terminal end is a common feature in simplistic opioid agonist molecules. So, yeah. Really simple opioid here. One aromatic ring, a saturated side chain off it terminating with a dimethylamine group, and a methyl side side chain at the beta carbon, and an ethyl side side chain at the gamma carbon (those two, I feel, mimic more ring presence even though they're not rings at all .... just the way they're positioned in space "fills out" the molecule if you can picture it).
The brand name of this drug, tapentadol, is Nucynta. It was released not long ago, and you can now be given a Rx for it for acute or chronic pain. It was placed in CII when clinical trials found equianalgesic doses of tapentadol and hydromorphone to be equally rated on the scales for "fun", "enjoyability", and "liking". Grunenthal knew tapentadol would be much more euphoric than tramadol which managed to get approved as a non-controlled substance, but they were angling for C-III. All hope for C-III was lost when the trial with tapentadol and hydromorphone equipotent doses showed equivalent enjoyability at equipotent doses and tapentadol was hammered into C-II with most other decent opioids. Tapentadol is not POTENT (I believe 200 mg tapentadol was equipotent to 8 mg hydromorphone, both orally) but apparently it can be pretty powerful at the right dose. I think 8 mg even oral hydromorphone would get me pretty high, so 200 mg tapentadol would probably get me pretty high also.
Some other somewhat simple ones are pethidine, ethylmethylthiambutene, ketobemidone, levorphanol, levomethorphan, and of course tramadol (but tramadol is a VERY weak opioid) ... but the above two impressed me the most (especially lefetamine).
If anyone can think of anything really simple that I missed or has any thoughts on these drugs ... shoot. I know not many folks have tried tapentadol (Nucynta) yet and that very few folks have or will ever get the chance to try lefetamine. For folks that get a chance to take Nucynta ... take a big enough dose. Use those figures from the clinical trial that landed it in C-II waters (8 mg hydromorphone equals 200 mg tapentadol, both oral) and calculate how much tapentadol you'd need to get high based on how much oral hydromorphone you'd need to get high. If you need 24 mg oral hydromorphone to get a solid strong buzz, then you'd need 600 mg tapentadol to get that same strength buzz, so it'd be unfair to take 100 mg tapentadol and proclaim "it friggin sucks, it's weak" in that situation.