How the hell does this work?

[Sphinx (Afterlife)]

With three asymmetric C atoms, the compound has eight possible stereoisomers. Four, two pairs of optical isomers, of the eight possible steroisomers would have cis arrangements of the substituents on C3 and C4.


So theres 8 possible stereoisomers, 4 are cis isomers.

When the two pairs were separated, one pair was found to be 5.3 times more potent than the other and 6300 times more potent than morphine. The more active pair was referred to as ohmefentanyl.


Thus based on what this says, 'true' Ohmefentanyl (as in what they refer to as 6300x Mphine) contains a mixture of 2 cis isomers, which, since it says are the 2 most active cis isomers, it is F9202 and F9204 or as we shall call 1a and 1b. 1a is something like 5000x Mphine and 1b is something like 13,000x Mphine. The other two cis isomers (1c and 1d) not found in 'true' Ohmefentanyl are both extremely weak relative to 1a and 1b.


A second sample, designated as RTI-4614-4 was determined to be a mixture of all four cis isomers and was shown to be 25,000 times more potent than morphine. In view of the differing activities and isomeric compositions of ohmefentanyl and RTI-4614-4, it was clearly necessary to resolve ohmefentanyl into its four stereoisomers.


So RTI-4614-4 is a mixture of 1a, 1b, 1c, and 1d, yet is like 4x the potency of Ohmefentanyl.

Now logic prevails and says, wait, if the strongest isomer in that mixture, is 13,100x Mphine, then even if the entire mixture of RTI-4614-4 was 100% purely of that isomer (1b) it could only be 13,100x Mphine, let alone when you add WEAKER isomers into the mix the potency, LOGICALLY speaking, should drop drastically, not increase TREMENDOUSLY.

So either the statement of RTI-4614-4 being 25,000x Mphine is perhaps the most horrificly mistaken calculation in the history of fuckin science, OR, it really is 25,000x Mphine.

In the case of the latter, my only real question is, HOW THE HELL DOES THAT WORK?

All 4 isomers have been shown to bind to different 'domains' of the mu receptor, is it possible that the two weak ones somehow synergise to an incredible lvl the analgesia of the two stronger? Is THIS what the above information has stated?? I cannot wrap my mind around that.

Is such a thing true for any other drugs and its isomers??

 

[Smyth]

Since RTI-4614-4 is composed of almost equal amounds of all 4 isomers, one would expect it to have a somewhat lower in vivo potency than the most active isomers. Although the mixture was in fact quite potent, its potency was approximately one-half to one-third that displayed by F2904. This comparison implied that the extraordinary in vivo activity of F9204 was in large responsible for the activity of the mixture.

I think there is discrepancy between the Chinese and American scientists ED50 values. Since in the American scientists paper they state that it was so strong they could only estimate F9204 lies in the region of 20-50KX morphine whereas RT4614-4 is thought to be 25KX morphine. Clearly since the Chinese scientists reported that F9204 has a potency of approximately 13KX morphine we can see that the two institutions values are not in agreement with one another.

 

[Sphinx (Afterlife)]

I think there is discrepancy between the Chinese and American scientists ED50 values. Since in the American scientists paper they state that it was so strong they could only estimate F9204 lies in the region of 20-50KX morphine whereas RT4614-4 is thought to be 25KX morphine. Clearly since the Chinese scientists reported that F9204 has a potency of approximately 13KX morphine we can see that the two institutions values are not in agreement with one another.

Yes but Wang and coworkers never did 1a-1d in vivo but rather just in vitro studies, unless I missed something that said otherwise, but alls I could see was they did in past do in vivo cis-1-A which is a mixture of (1c, 1d).

Whilst Rothman and coworkers did RTI-4614-4 in vivo and found that the weaker 1c despite showing in vitro far less mu selectivity and binding had something to do with its efficacy and psuedoirreversible qualities that led it to be extremely powerful in vivo

Now these guys got the erratum for Table 2, in which 1c is actually 1a and vice versa. I have no clue if throughout the entire document they always called 1c as 1a and 1a as 1c. I assume not, because in all the other tables they have the correct data for the correct isomers so its kinda confusing to know when they mean 1a is 1c and when 1c is 1a. Fuckin douche bags.

Regardless of either it is, arent primates among the most opiate sensitive? in vivo is more the data of real meaning in these regards. Wang and coworkers as far as I could tell never studied all the isomers in vivo, but their in vitro data we are comparing to Rothmans in vivo arent we? That doesnt necessarily correlate.

Of course they could just be really far off in their 'estimate' of xM potency

 

[Smyth]

I'm reading into this but in the mean time you'll have to judge it for yourself. I hope we are at least clear that F9204 is FAR superior to RTI-4614-4 although the latter is still credible. Also any such bullshit as 20,000X morphine is blown out of proportion. The Chinese scientists did a good job to try and keep a lid on the suggested potency. The US scientists even conceed that it is in the same ballpark as carfentanil, so we are talking on the order of a few micrograms IV in humans? Also I think it says that ohmefentanyl lasts about 90 min duration, so it is approximately double that of carfentanil which is marginally shorter than fentanyl. Hope this helps