Lefetamine

[haribo1]

I've been interested in this compound for years. After the Second World War, the Japanese public, desperate to rebuild their shattered economy & infrastructure went on one almighty binge to help them work. Amphetamines were cheaper than food and allowed the beaverlike Japanese to work even harder. The drug they went for wasn't (meth)amphetamine, ritalin or anything like. It was this:

OK, it looks sort of PEA derived but its action is quite interesting. Not only does it stop the reuptake of dopamine & norepinephrine but it also binds with the opiate receptors. Now, it doesn't follow the morphine rule (1-aromatic system 2-Quaternary carbon 3-two carbon chain, 4 tertiary amine) but then again, their are a few other agents that don't. Tilidine being a good example.
It is reported to have both stimulant & 'opiate like' effects everywhere I read. It produces opiate tolerance & dependance that naloxone precipitates withdrawal syndrome. It is usually described as a 'partial agonist'.
So, stimulant AND opiate. Sounds like a speedball with one chemical, doesn't it. I know the N,N dimethyl has replaced with diethyl & ortho morphilino methyl homalogues but no details.

I'm thinking that this could be a very interesting compound, if skillfully manipulated.

I'm wondering if anyone has researched or has access to research papers on this and related structures.

 

[wungchow]

i remember seeing this badboy in the Merck Index. pretty interesting molecule

 

[phase_dancer]

Methamphetamine was a big problem post war Japan."

Patterns of Illicit Psychostimulant use in Australia by Wayne Hall and Julie Hando

...Amphetamines

...The problems caused by chronic heavy use of amphetamines became apparent in the post war period during a succession of epidemics of amphetamine use. The earliest and most dramatic occured in post-war Japan between 1945-1954 (Brill and Hirose, 1969) when large surplus stocks of injectable methamphetamine were dumped on the domestic market and heavily promoted by over-the-counter sales. At it's peak 1.5 million persons in Japan were estimated to be injecting methamphetamine (Grinspoon and Hedblom, 1975)

The problem that brought the epidemic to official attention was the occurence of psychiatric disorders among heavy users. The Japanese Government responded with severe restrictions on the availability of methamphetamine, the introduction of penal sanctions against use and a strong public propaganda campaign against the use of methamphetamine. This combination of actions enjoyed strong public support and so reduced the prevalence of methamphetamine use, concentrating it among minority groups and deviant inner city youth (Brill and Hirose, 1969, Hemni 1969). Methamphetamine and inhalant use have continued to be problems among these groups, albeit at a much lower level (Suwaki, 1989)...

Refs:

Brill H and Hirose T (1969) "The rise and fall of a methamphetamine epidemic: Japan 1945-1955". Seminars in Psychiatry 1: 179-193

Grinspoon L and Hedblom P (1975) "The speed culture: amphetamine abuse in America". Harvard University Press, Cambridge Mass.

Hemni T (1969) How we handled the problem of drug abuse in Japan. In Sjoqvist F and Tottie M (eds) "Abuse of central stimulants" Ravens Press, NY: 147-153

Suwaki H (1989) "Addictions: What's happening in Japan?" International review of psychiatry 1: 9-11

Here's the Merck entry for Lefetamine. Although I can see how stimulant claims stem from the structure, no mention is made of any stimulant properties.

Title: Lefetamine
CAS Registry Number: 7262-75-1
CAS Name: (aR)-N,N-Dimethyl-a-phenylbenzeneethanamine
Additional Names: (-)-N,N-dimethyl-1,2-diphenylethylamine; (-)-N,N-dimethyl-a-phenylphenethylamine
Molecular Formula: C16H19N
Molecular Weight: 225.33.
Percent Composition: C 85.28%, H 8.50%, N 6.22%
Literature References: Centrally acting analgesic with stereochemical resemblance to morphine, q.v. Prepn and activity: K. Ogiu et al., J. Pharm. Soc. Japan 80, 283 (1960); eidem, JP 61 23087 (1961 to Res. Found. Practical Life). Absolute configuration: M. Nakazaki, Chem. & Ind. (London) 1962, 1577. NMR data indicates 22% eclipsed conformation which appears to enhance stereoselectivity for morphine receptors: T. Sasaki et al., J. Med. Chem. 9, 847 (1966). Pharmacology: H. Nakamura, M. Shimizu, Arch. Ind. Pharmacodyn. Ther. 221, 105 (1976). Clinical study: J. P. Famaey, T. L. Peeters, Brux. Med. 56, 21 (1976). Analgesic activity: M. Nozaki et al., Life Sci. 33, Suppl. 1, 431 (1983). Opiate agonist activity: M. Graziella de Montis et al., Pharmacol. Res. Commun. 17, 471 (1985).
Properties: bp6 142-147°. [a]D20 -124.2° (ethanol).
Boiling point: bp6 142-147°
Optical Rotation: [a]D20 -124.2° (ethanol)

Derivative Type: Hydrochloride
CAS Registry Number: 14148-99-3
Trademarks: Santenol (Coop Farm); SPA (Santen)
Molecular Formula: C16H19N.HCl
Molecular Weight: 261.80.
Percent Composition: C 73.41%, H 7.70%, N 5.35%, Cl 13.54%
Properties: mp 218-219°. [a]D20 -91.7° (water).
Melting point: mp 218-219°
Optical Rotation: [a]D20 -91.7° (water)

Therap-Cat: Analgesic.

 

[Jamshyd]

Not only that, but I believe it also NMDA-antagonist properties, making it insanely close to Ketamine in its profile.

I've been obsessing about it for a while too. Apparently there was a brief "problem" with it in Italy last century. So it must be abusable in one way or another. Why no one bothered make it is beyond me, since according to what I've read, anyone who can make MDA can make it.

(then again the same applies to TMA2 and MMDA, but you don't see these on the street. I guess demand/supply trumps curiousity )

 

[kidamnesiac]

any indications on how chirality affects effects?

 

[haribo1]

The usage of lefetamine was bigger than that of methamphetamine in Japan, but since it was already OTC before the war, the exact usage levels were not recorded. I did not know about it's NMDA effects, but that makes it even MORE interesting. I wonder if the other isomer is the stronger NMDA antagonist?

 

[getreal]

I want to obsess about it too.

But I dont understand all the chemistry giberish??

 

[fastandbulbous]

I posted something about it ages ago (can't remember where-most probably here) suggesting the similarity between lefetamine and the arylcyclohexylamines - ie that the benzyl group seems to partially substitute for the cyclohexyl ring as they both show a significant degree of NMDA antagonism. In this way, lefetamine is analagous to 1-phenyl-N,N-dimethylcyclohexylamine (so that the lefetamine derivative 1,2-diphenyl-1-(1-piperidyl)ethane is analagous to PCP)

 

[nuke]

unscheduled analogues:

Pyrrylphenylethanones related to cathinone and lefetamine: synthesis and pharmacological activities.
Massa S, Di Santo R, Mai A, Artico M, Pantaleoni GC, Giorgi R, Coppolino MF.

Dipartimento di Studi farmaceutici, Universita di Roma, La Sapienza, Italy.

The synthesis of various pyrrylphenylethanones resembling cathinone and lefetamine is described starting from 2-chloro-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethan-1-one. Some derivatives showed good antinociceptic activity, comparable to that of morphine. The neuropsychopharmacological profile of title compounds has been also studied to explore their action on C.N.S.

PMID: 1417455 [PubMed - indexed for MEDLINE]

 

[haribo1]

So something like this except their is no trichloro grouping?

 

[nuke]

Not exactly, this is the first one they mention:

 

[hussness]

^Wouldn't that be a potential alkylator?

 

[nuke]

Probably.. I wonder what the rest in the series look like?

More:

Synthesis, neuropsychopharmacological effects and analgesic-antiinflammatory activities of pyrrole analogues of lefetamine.
Massa S, Stefancich G, Artico M, Corelli F, Silvestri R, Pantaleoni GC, Fanini D, Palumbo G, Giorgi R.

Dipartimento di Studi Farmaceutici, Facolta di Farmacia, Universita degli Studi di Roma La Sapienza, Italy.

The synthesis of pyrrole analogues of the analgesic drug lefetamine is reported. These derivatives bear the 1-phenyl-2-(1H-pyrrol-1-yl)ethylamino moiety. Compounds were evaluated for analgesic activities in mice by the hot plate and Randall-Selitto tests. Antiinflammatory activity was tested by the carrageenan-induced rat paw edema method. General neuropsychopharmacological effects were also screened. The most interesting compound, N,N-dimethyl-1-phenyl-2-(1H-pyrrol-1-yl)ethylamine, showed an analgesic effect comparable to that of lefetamine, but devoid of the neurotoxicity of this drug.

PMID: 2604832 [PubMed - indexed for MEDLINE

...which also indicates lefetamine is neurotoxic.

 

[haribo1]

This is a precursor, is it not? Is the chlorine replaced by an amine?

 

[nuke]

I think so. It's be pretty easy to substitute different alkylamines from the chlorine.

 

[hussness]

I wonder if the N-methylpyrrolethanone moiety mimics the proline residue found in the second position of the endomorphins.
nuke - would you mind pming me the article?

 

[nuke]

I would if I had it, I don't know where I'd find Italian pharmacology journals around here. :/ If anyone else has access I'd love to see it..

 

[haribo1]

Does the journal say what reactions are done to this precursor? I'm thinking dimethyl amine or diethyl amine. Isn't antinociceptic activity related to NMDA action? It's not opiate receptor binding that controls it's pain-killing effects?
Looking at it, is it an amphetamine type stimulation or a nicotine receptor type stimulation? What is an effective dose, for example.

 

[Jamshyd]

Just a caveat: Ever since I tried 2-Aminoindan (see TR forum for a recent experience I posted there), I have become warry of places where pharmacologists blab about something "comparable to morphine".

 

[haribo1]

Just a caveat: Ever since I tried 2-Aminoindan (see TR forum for a recent experience I posted there), I have become warry of places where pharmacologists blab about something "comparable to morphine".

I think we all keep this in mind. I mostly look for trip-reports here or on Erowid.