Tramadol analog N-substitution

[pr0d1gy]

I know surely there must be a plethora of literature about various derivatives of tramadol having different n-substituents. I don't have experience searching this kind of literature and frankly don't want to use the search engines available to me to do so. I am wondering what changes in activity might occur if the dimethylamino moiety were altered to diethylamino or cyclicized to piperidine or pyrollidine.

I'm mostly interested in the possibility of the n-diethyl analog. Based on data from some pethidine derivatives I think this may hold some possibility of being worthwhile. Would these and their o-demethylated counterparts be weaker mu-agonists?

 

[sekio]

I can't see anything on Reaxys. The diethylamino-, piperidino-, and pyrrolidino- analogues are unknown!

 

[pr0d1gy]

I can't see anything on Reaxys. The diethylamino-, piperidino-, and pyrrolidino- analogues are unknown!

I found a patent on scifinder which includes the diethylamino analog but nothing in terms of biological data. I'd have thought the diethylamino analog would be known somewhat. It doesn't seem like an overtly terrible idea. It seems reasonable to postulate it wouldn't be vastly different from tramadol. I don't know if it would be more or less potent, but my money is on less. As you said these do appear to be unknown so only one way to find out.

I'm discouraged by the absence of literature, but still tempted by the diethylamino analog in particular. I plan to try it out by titrating slowly up to 40mg to gauge if it has any analgesic value. Plan to take low dose benzodiazepine concurrently in case the diethylamino analog has greatly more powerful pro-convulsant effects. Will report back in few days. Any additional input in the mean time would be appreciated although it appears for the most part it would be theoretical.

edit: Looking at the original Grünenthal patent (in German), they actually claim that the dimethylamino substitution is essential for activity. Other literature seems to dispute this to a certain extent, so I don't believe it 100%.

 

[Hammilton]

This has probably been looked at, but does a phenethyl tail on the amine make for a real potent tram analogue?

 

[pr0d1gy]

There is an article from a Chinese pharma journal that investigates n-phenylalkyl tramadol analogs, including the phenethyl and methylphenethyl analogues apparently. I don't have access to the complete article, but the abstract seems to suggest that these analogues or close derivatives of them were active. Can't say for sure though, the abstract is incomplete and ambiguous. It also doesn't mention which substitution in particular they found to retain some activity

.http://www.nature.com/aps/journal/v36/n7/full/aps2014171a.html