Lefetamine Derivatives

[Hammilton]

Lefetamine Analogues (Based Entirely on Published Research)

(edit: I just realized that there's really no point to this thread, well, aside from posting some evidence taken from some papers on the subject. I just haven't gotten there yet, but I'll get to the reason for all of this in my next update)

I started working on this 24 hours ago, but had a particular bad period of memory loss and found that I couldn't possibly finish it at the time. When I came back to it this morning, I realized that if I posted it in the form it had taken, you'd all think I had smoked a ton of pot and tried writing. So this will be my second go of it, but I think the extra time has allowed me to make it a lot better than it would have originally have been.

This thread is somewhat relevant to nuke's DMPP thread, except that this is based off of (what I believe is) Masso's follow-up to the original paper that looked at non-neurotoxic lefetamine analogues (among others). All of the papers referenced are available for download (contact me for assistance here if you need it). The papers I will be referencing will be the following:

1. Masso, et al Arch. Pharm. vol325(iss8, I think!) pg 403-409 titled "Pyrrylphenylethanones Related to Cathinone and Lefetamine:
Synthesis and Pharmacological Activities"
2. Takahashi, et al Chem. Pharm. Bull. 34(5) pg 2071-2077 titled "Asymmetric alpha-substituted Phenethylamines. VI. Synthesis and Analgesic Activity of Optically Pure (R) and (S)-N-alkyl-1-cyclohexyl-2-phenethylamines
3. Japanese Patent Office No. 62059246 titled: "Optically Active 2-Phenethylamine Derivative Having Analgesic Activity Comprising Same as Active Ingredient" (minor reference, not all that useful, either)

I'm going to divide this post into two halves, the first half dealing with derivatives with opioid like effects, and the latter dealing with derivatives with only amphetaminergic effects.

Derivatives with Opioid-like Effects

From Ref. 2, compounds 9e, 9f, 9i-k, and 9m were all more potent than (-)-pentazocine as analgesics. However only compounds 9f, 9J, 9K and 9n had their analgesic activity antagonised by naloxone. Of those with opioid effects, 9f, 9j and 9k are more potent than pentazocine.

Reference 1 is a bit more interesting because they go into much wilder structures. Compound 10 of this paper, for instance, is 2-(2-(1-methyl-1H-pyrrol-2-yl)-2-oxo-1-phenylethyl)isoindoline-1,3-dione. What an interesting structure! While this structure has strong analgesic effects, in one section they report that it has no effects on the behaviorial profile, but in another they report it as having 100% Partial Protection against seizures [defined as seizures but no deaths].

Structures that seem to have opioid effects though (decrease in spontaneous motor activity and analgesic effects) are 11, and 12a. Interestingly, going from dimethylamino (12a) to diethylamino (12b) virtually abolishes analgesic activity.

Unfortunately, Ref. 1, the more interesting paper doesn't go into much detail as regarding opioid effects, and neglect any sort of naloxone test.

All compounds from Ref. 1 (except a small handful, including the cool one, 10) decreased spontaneous motor activity, but they weren't very strong analgesics, or weren't analgesics at all. 10 was a strong analgesic, but whatever it's analgesic activity is the result of, opioid effects seem unlikely.

Even more unfortunately, Ref. 2 attempts only the most basic alterations to the core structure (alpha-cyclohexyl-beta-phenyl-ethylalkylamines) are tested at all- it's all N-substitutions. Given the theory put forward in the few lefetamine papers I've seen, that lefetamine and it's derivatives obtain their analgesic activity from their resemblance to a pared down morphine, they neglect the most interesting substitutions in testing that theory. Testing the para-hydroxyphenyl, or 1-cyclohexan-4-one analogues is entirely ignored. They don't even test N-phenylethyl. 4-(2-(4-hydroxyphenyl)-1-(methyl(phenethyl)amino)ethyl)cyclohexanone (or the N-demethylated version) would have made for really interesting structures to test. There does exist a paper (the full copy I haven't seen) that documents the analgesic activity of the alpha-phenyl-beta-(4-hydroxyphenyl)ethylaminel, but I don't remember if they were N,N-dimethyl as in lefetamine or not.

What both ref's tell us is that N-substitution is not a reliable predictor of opioid activity of lefetamine derivatives. In Ref. 1, N,N-dimethyl is very active. N,N-diethyl is entirely inactive. In Ref. 2, those with definite opioid activity (as measured by naloxone antagonism), 9f,j,k and n were N-iso-Propyl, N-methyl-N-cyclopropyl, N-propyl, and N-methyl respectively.

Unfortunately, though, 9n is an (S) isomer, and as such, it's not very useful here (because as an (S)-isomer, it wouldn't be expect to have much if any mu affinity, though apparently it does have some). It is interesting for other reasons, though.

Not just a little useless, but pretty much entirely so.

Derivatives with Amphetamine-like Effects

Compounds 9m and 9n (Ref. 2) had exciting activity, indicative of potent amphetamine like activity. How potent is unfortunately unknown because they don't go into any detail on the subject.

Mostly I'm going to focus on Ref. 1 here because this reference went into the most detail regarding stimulant activity (and the least regarding opioid effect).

Unlike DMPP from nuke's thread on the topic, which focused on N,N-dimethyl-2-(1-methyl-1H-pyrrol-2-yl)-1-phenylethanamine, this paper focused on beta-keto derivatives of N,N-dimethyl-1-phenyl-2-(1H-pyrrol-1-yl)ethanamine. You'll have to download the cmx file to see exactly what I'm taking about, but where the latter connected the beta-pyrrole to the 1-phenylethanamine backbone by the pyrrole nitrogen, this paper connects them by a carbon adjacent to the pyrrole nitrogen (and adds a methyl to the pyrrole nitrogen).

I think the idea of these was that they would be non-neurotoxic lefetamine derivatives, but oddly, there is no mention of whether they were neurotoxic or not. Because I have not seen the full version of Massa's 1989 Farmaco paper, I don't know if these were looked at for neurotoxicity in that paper or not.

I'll continue this later. It's late and I want to post this before I get tired and my memory gets worse that it's already gotten. It's amazing the difference two hours of thinking does to me.

download cdx: http://www.yourfilehost.com/media.php?cat=other&file=Lefetamine_Derivatives.cdx
image of the cdx (.png)
http://www.yourfilehost.com/media.php?cat=image&file=Lefetamine_Derivatives.png

 

[LuxEtVeritas]

Certainly not worthless and a good start...
Notably I am almost tired of LEF due to its misguided Holy Grail status in past posts, but this is a meaningful direction of exploration fo the structure and its cogeners...or as meaningful as most anything on here is

 

[Hammilton]

thanks

Big ups to Enkidu who has ordered the paper Nuke referenced in the DMPP thread. That will definitely improve this overview.

^Yeah, lefetamine has been imbued with a status not really deserved. The whole series has potential, certainly, lefetamine itself doesn't interest me very much. I'm much more interested in lefetamine derivatives that lack stimulant activity but maximise mu opioid receptor affinity. Or at least those whose stimulant activity is minimal.

It's the whole speedball in one drug thing, which seems pointless when speedball in two drugs is so much more accessible.

Still, it surprises me that lefetamine derivatives haven't showed up as RC's yet. They're not hard to make, even optically pure (phenylglycine!). I'm not sure if the various pyrrol derivatives covered in the Massa paper I cover here, the Farmaco paper I'll hopefully go into sometime next week.

Do you think that 1-(1-methyl-1H-pyrrol-2-yl)propan-2-amine or 1-(1H-pyrrol-1-yl)propan-2-amine (the backbones of the two main structures from the Masso papers) would be considered amphetamine analogues? Pyrrol seems sufficiently different than phenyl, but I'm not certain. I mean, courts have rules that 1,4-BD isn't a GHB analogue, and the DEA even says that CP 47,497 isn't a THC analogue, so it seems that perhaps they're going to stick to what the law was intended to cover- very slight modifications (adding a methyl here, a methoxy there, etc).

I'm not planning on putting forward any big questions for conversation with this thread, but hopefully a concise overview of what's been published will increase the level of discussion.

I'm still pissed that the alpha-cyclohexyl-phenethylamine paper didn't do a very good job. No binding assay, no naloxone challenge. Based upon the prevailing theory that lefetamine has opioid activity because of it's resemblance to a pared down phenanthrene, they really should have at least tried 4-hydroxyphenyl and cyclohexan-4-one together with N,N-dimethyl or N-methyl N-phenethyl (given the way it increases opioid affinity with the phenanthrenes, why not??)