(Hive Bee)
12-07-03 18:07
No 475219
(Rated as: excellent)
Recently there have been a number of discussions on butanamines:1 both the amphetamine analogue 2-amino-1-phenylbutane, or aephetamine2, and also the methamphetamine analogue 2-methylamino-1-phenylbutane, or methaephetamine.2 Until now, no synthesis of the latter had been published at the Hive.
The four step procedure below begins with benzene, and proceeds via the 'butanamine methcathinone' analogue, the synthesis of which has been posted, although a modified version follows. The reduction of this gives the ephedrine analogue, finally undergoing a standard HI/P reduction to give the title product.
The method as stands has little use for ring substituted amines because of HI's ability to cleave aromatic ethers. Notable exceptions are active compounds which don't contain alkoxy groups; the use in the initial acylation step of either fluorobenzene/propionyl chloride to give 4-fluoromethamphetamine as the final product, or indane/propionyl chloride to give the untested [?] 'indanylmethamphetamine', or N-methyl IAP.3 The combination of benzene/propionyl chloride will of course produce racemic methamphetamine, although propiophenone is extremely cheap, and purchasing this would be a nice way of cutting out a step.
Experimental
Butyrophenone
Synthesis exactly as the acylation described in Post 465794 (Kinetic: "2-methylamino-1-phenyl-1-butanone", Stimulants). Yield: 89%.
Molecule: Butyrophenone ("CCCC(=O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butanone4
300mmol butyrophenone (44.5g, 43.5ml)
310mmol bromine (49.5g, 15.9ml)
~750mmol methylamine as a 30% aq. solution (85ml)
330mmol 37% HCl (27ml diluted to 300ml)
DCM
Toluene
Sodium bicarbonate solution
Water
50% aq. NaOH solution
Magnesium sulfate
The bromine was added a well stirred solution of the butyrophenone in 100ml DCM, dropwise over 15 minutes. Stirring was continued for a further 15 minutes, then the solution was washed with 100ml water and 3x100ml sodium bicarbonate solution.
The almost colourless organic layer was placed back in the flask, and aqueous methylamine was added over 10 minutes. Stirring was continued for 4 hours after addition.a The solution was washed with 3x200ml water, then extracted into 3x100ml dilute HCl. The combined acidic extracts were washed with 2x100ml toluene, then cooled and basified to pH 11 with ~16ml NaOH solution. The liberated freebase was extracted into 3x50ml DCM, and the combined extracts were washed with 2x100ml water then dried over MgSO4. The solvent was cautiously removed,b to leave the product as a clear yellow oil.
Yield: 38.7g (219mmol, 73%)
aThe exothermic reaction rose to reflux, and had cooled to room temperature by this time.
bA low temperature ensures minimal thermal decomposition of the aminoketone freebase.
Molecule: 2-methylamino-1-phenyl-1-butanone ("CNC(CC)C(=O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butanol5
100mmol 2-methylamino-1-phenyl-1-butanone (17.7g)
50mmol NaBH4 (1.9g) in 10ml water containing 25mg NaOH6
Methanol
Acetic acid
DCM
50% NaOH solution
Water
Brine
Magnesium sulfate
To a well stirred solution of the aminoketone in 50ml methanol, cooled to 0oC via an ice bath, was added dropwise a solution of NaBH4 in water, whilst not allowing the temperature to rise above 15oC. The clear solution quickly became turbid, and the initial yellow colour faded to almost white. The reaction was stirred with ice bath cooling for half an hour after addition, then at room temperature for a further hour. Acetic acid was then added until fizzing ceased, then all was poured into 200ml water. NaOH was added to bring the pH to 12, causing a voluminous creamy white precipitatea to form, which was extracted into 100ml then 2x50ml DCM. The combined extracts were washed with 100ml water, 100ml brine, then dried over MgSO4. Removal of the solvent gave a pale solid which was distilled at 134-137oC to give the aminoalcohol as sparkling, waxy white crystals.b
Yield: 14.8g (83mmol, 83%)
aThe amount of precipitate was unprecedented, and far more than the amounts formed with similar borohydride reduction attempts (either DCM/water/PTC (67%), or aminoketone HCl/water (88%, but messy)). It is know that in methanol, cathinones racemise, presumably via an enolate intermediate. Maybe in this case the borohydride is instead reducing the double bond of the enolate, hence affecting the stereochemistry of the product: ephedrine is soluble in water whereas pseudoephedrine is much less so.
bNone of which made it to the receiving flask, and were very difficult to scrape from the condenser.
Molecule: 2-methylamino-1-phenyl-1-butanol ("CNC(CC)C(O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butane; Methaephetamine7
80mmol 2-methylamino-1-phenyl-1-butanol (14.3g)
130mmol red phosphorous (4.0g)
260mmol HI as a 57% aq. solution (34ml)
85mmol 37% HCl (7ml)
50% NaOH solution
Methanol
Ether
Water
Magnesium sulfate
A well stirred solution of the aminoalcohol in 40ml methanol was treated with HCl.a After stirring for 10 minutes, all volatiles were removed under vacuum. The HI and phosphorous were added in one batch, and the reaction heated to reflux (approx. 115oC) for 36 hours. The reaction mixture was then cooled, diluted with 200ml water and filtered. The solution was washed with 60ml toluene,b then basified to pH 12 with NaOH. The pale, clear freebase was extracted with 2x50ml ether, and the combined extracts were washed with 2x100ml water, dried over MgSO4 and the solvent removed to give the title product as a clear, almost colourless oil.c
Yield: 9.9g (76%)
aUse of the freebase instead of a salt will lead to a lower yield even if an extra equivalent of HI is added, as it effectively reduces the concentration of free HI to ~43%, assuming the density remains the same.
bThis was due to a toluene shortage, 2x100ml toluene is recommended.
cThis will be dissolved in IPA, neutralised with HCl, and precipitated with ether. Undesirable aziridines/iodo compopunds etc. will be removed by recrystallisation: methanol/ether, or boiling acetonitrile8 will be attempted first.
Molecule: 2-methylamino-1-phenylbutane ("CNC(CC)Cc2ccc1c1c2 ")
Acknowledgements
Many thanks to Nemo_Tenetur, wherever he is, for providing excellent information which got me into clandestine chemistry in the first place, and whose synthesis of a Pyrovalerone analogue the first two steps were based upon. It also goes (almost) without saying to thank Rhodium and all the other Mods, since I wouldn't have been able to post any of this without the wonderful Hive.
References
1 Post 461403 (Chimimanie: "Ariadne and the Butanamines", Serious Chemistry); Post 470499 (Vitus_Verdegast: "phenyl-2-nitrobutene (P2NB) data needed...", Chemistry Discourse)
2 Post 471099 (moo: "Maybe it should be called aephetamine, as in a", Novel Discourse)
3 ../rhodium /iap.htm
4 Post 289410 (foxy2: "Methcathinone and ephedrine from propiophenone", Stimulants)
5 Post 433684 (Barium: "You can reduce ketones or aldehydes with ...", Methods Discourse)
6 Post 426052 (Barium: "Novel high-yielding C=C reduction of nitrostyrenes", Novel Discourse)
7 ../rhodium /meth.hi
8 Post 454897 (Rhodium: "Recrystallization of MDMA.HCl for Purity", Methods Discourse)
(Stranger)
12-07-03 22:05
No 475253
Great work! Hope you will also rapport about its potency in vivo.
I see you spared some of the 2-methylamino-1-phenyl-1-butanone and done it before also.
I’m very much interested about its activity?
Btw, do you know that the alpha-ethynyl-PEA is supposedly also active:
“The alpha-methyl group of amphetamine itself can be replaced by allyl, ethyl, or ethynyl groups of electron-donating character, without deleterious effects on centrally-mediated actions [some refs], but replacement by electron-withdrawing groups, such as cyano [ref] or trifluoromethyl [ref], abolishes amphetamine-like properties.”
From page 74 of: Brimblecombe, R.W.; Hallucinogenic agents. Bristol: Wright-Scientechnica 1975.
I'm only mentioning this because this compound should be easily prepared by reacting the commercially avaiable sodium acetylide with the shif base of phenylethanal:
Ph-CH2-CH=NR + NaCCH ---> Ph-CH2-CH(NHR)-CCH [where R: H or Me]
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Chief Bee)
12-08-03 00:44
No 475273
Nicodem: What about those references - could you spell them out?
(Hive Addict)
12-08-03 03:40
No 475311
Congratulations Kinetic!! What an excellent job you've done!
I also would like to hear some bioassay details.
SWIM used phenyl-2-aminobutane a couple of times now, and the conclusion is that it is only a mild stimulant, certainly less potent than amphetamine, but useful as eg. a study aid.
Post 472059 (Vitus_Verdegast: "bioassay", Chemistry Discourse)
The N-methylamino compound should be more potent however..
The Other War (http://www.markfiore.com/animation/drug
(Active Asperger Archivist)
12-08-03 04:03
No 475316
You are correct about both instances. The N-methyl is more potent, but still lacking in terms of strength (vs amphetamine). Both are nice though.
It's kinda like super-dosing caffiene- not much for the euphoria, but good for a steady awake/awareness.
Act quickly or not at all.
(Stranger)
12-08-03 23:36
No 475500
(Rated as: good read)
Sorry Rhodium. I wasn't sure anybody would care for new challenges so soon so I spared some typing. Here I copied the text and added the references:
“The alpha-methyl group of amphetamine itself can be replaced by allyl, ethyl, or ethynyl groups of electron-donating character, without deleterious effects on centrally-mediated actions [1,2], but replacement by electron-withdrawing groups, such as cyano [3] or trifluoromethyl [4], abolishes amphetamine-like properties.”
[1] Burger, Zimmermann, Ariens (1966), J. Med. Chem. , 9, 469.
[2] Shamano, Hitchens, Goldstein, Beiler (1968), Arch. int. Pharmacodyn. Ther. , 172, 251.
[3] Pinder, Burger, Ariens (1970), Arzeim.-Forsch. , 20, 245.
[4] Pinder, Burger (1967), J. Pharm. Sci., 56, 970.
I very much recommend this book (Hallucinogenic agents). There are even more info on the side chain modifications for the psychedelics. I was so inspired by a modification that I’m planning a new project: phenoxyethylamines and phenoxyisopropylamines. Some of the phenoxyethylamines were found active hallucinogens in animal test. The one shown below was twice as potent as mescaline in some EEG tests on cats, but I’m still searching for the original studies (very old and inaccessible publications). Maybe the phenoxyisopropylamines would be even more potent. They must be so extremely easy to prepare starting from various phenols. There are some hints from Medline for the possibility that phenylthioisopropylamines may also posses some activity, even thought the homoamphetamines (Ar-(CH2)2-CH(NH2)-Me) are essentially inactive (the DOM homologue was found to be 100times weaker and others even much less active).
Molecule: a hallucinogenic phenoxyethylamine ("c1(cc(c(cc1Cl)Cl)OC)OCCN")
If anybody can find and post them, these are the refs for the phenoxyethylamines:
Julia, M. and de Rosnay; European Journal of Medicinal Chemistry, 4 (1969), 334.
Julia, M. and de Rosnay; European Journal of Medicinal Chemistry, 5 (1970), 337.
(European J. of Med. Chem. stil had the title Chim. Ther. in those times)
Rougeul, A.; Laval. med., 40 (1969), 37.
Rougeul, A. and Verdaux, J.; Rev. Can. Biol., 31 (1972), 49.
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Stranger)
02-02-04 01:15
No 485915
Nicodem, you always provide very interesting and novel info...
They must be so extremely easy to prepare starting from various phenols.
Indeed, they are extreamly easy to prepare. A word of caution. There is some structural similarity to chlorophenoxy herbicides, for instance 2,4-D - (2,4-dichlorophenoxy) acetic acid - a very (neuro)toxic pesticide.
http://www.epa.gov/ttn/atw/hlthef/di-oxy
2,4-D is a herbicide used on a number of crops. At high concentrations it affects the central nervous system (CNS) in humans, with symptoms including stiffness of arms and legs, incoordination, lethargy, anorexia, stupor, and coma. 2,4-D is also an irritant to the gastrointestinal tract and skin in humans. Chronic (long-term) oral exposure to 2,4-D results in effects on the blood, liver, and kidneys in animals. Several human studies have suggested an association between exposure to 2,4-D (and other herbicides) and an increased incidence of tumor formation. However, it is not clear whether this represents a true association, and, if so, whether it is specifically related to 2,4-D. Some studies have reported increased incidences of tumors in orally exposed animals. EPA has not classified 2,4-D as to its human carcinogenicity.
But, who knows, amines might be harmless...
http://www.epic.org/privacy/terrorism/hr
(Hive Bee)
02-02-04 11:11
No 486024
Yes Captain, I was aware of the similiarities with that herbicide and that the metabolite of the phenoxyethylamines are indeed phenoxyacetic acids. That herbicide however does not seam more treathening than many pharmaceuticals(speaking about acute toxicity, the chronic toxicity is more freightening). Thats why I would preffer to skip the oxyethylamine side chain and check the oxyisopropylamines instead. But unless somebody can get those papers I will soon forget about them. So, again, if there is any bee with access to these ancient papers please post them:
Julia, M. and de Rosnay; European Journal of Medicinal Chemistry, 4 (1969), 334.
Julia, M. and de Rosnay; European Journal of Medicinal Chemistry, 5 (1970), 337.
(European J. of Med. Chem. stil had the title Chim. Ther. in those times)
Rougeul, A.; Laval. med., 40 (1969), 37.
Rougeul, A. and Verdaux, J.; Rev. Can. Biol., 31 (1972), 49.
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Chief Bee)
02-05-04 17:50
No 486598
(Rated as: excellent)
Selective monoamine oxidase inhibitors. Compounds derived from phenethylamine and 1-phenoxy-2-aminopropane.
Y. Kumar, L. Florvall, et. al.
Acta. Pharm. Suec. 20, 349 (1983) (../rhodium/pdf /maoi-ampheta
Abstract
4-Alkoxyphenylalkylamines (1-10). 3- and 4-trifluoromethylphenethylamines (11-14) and 1-phenoxy-2-aminopropanes (15-22) were synthesized and tested for monoamine oxidase (MAO) inhibitory effects in vitro and after oral administration in vivo with particular attention to any selective effect on the A form of MAO. The compounds were, to varying degree, more potent in inhibiting the deamination of 5-hydroxytryptamine (5-HT) than phenethylamine. i.e. they are preferential MAO-A inhibitors. The most potent compounds in vitro were 3-(4-ethoxy-2-methylphenyl)-1-methylprop
The Hive - Clandestine Chemists Without Borders
(esoteric)
02-05-04 21:22
No 486637
2,4 D is one of the least hazardous of the herbicides.
Safety first, of course:
this has been around for decades, people have fallen into vats of it, and there is enough reasearch data thru
accidental exposure to not get real excited about it.
I was addressing this issue in a presentation to some worried
folks who were sure that since 2,4,5,T ( (2,4,5-trichlorophenoxy)acetic acid) was so similar
2,4 D, (2,4-dichlorophenoxy)acetic acid) that it must be about as bad...
The problem is that 2,4,5T was the principle component of agent orange, the defoliant implicated in a huge # of diseases (Hodgkin's lymphoma, etc...)
and apparently it is near impossiblt to make 2,4,5 T without
some side dioxans of intense carcinogenicity.
anyway, wandering, 2,4D can for some reason be manufactured
without the dioxan side-load.
dwarfer
(Hive Bee)
02-06-04 00:41
No 486703
I should include an update before this thread becomes devoted entirely to herbicides.
The aminoketone 2-methylamino-1-phenyl-1-butanone was first synthesised over a year ago as an intermediate, but such a small amount was isolated that a bioassay was the only viable next step. The initial consumption quickly developed into a ritualistic cycle of making and taking, and was such that it held back the reduction to methaephetamine by almost a year.
I seem to recall that before the spectacular tolerances associated with this overuse had built up, a dose of 100mg orally was very pleasant, for me and others, and would keep me awake all night. After some time, I found myself almost immune to even 300-500mg consumed intranasally, though still spent almost the entire summer awake on it, with a cycle of 5 days awake followed by 2 days sleep, for a couple of months. I lost around 11kg bodyweight (from an initial ~65kg) which I have since regained, and a large amount motivation, which I have not.
I tried methaephetamine with a cautious dose of 20mg orally about a week after starting this thread. Nothing happened. I soon found some 200mg intranasally was required to give a high; though it didn't seem a 'high' as such, the classic stimulant signs were all there. Until I lay down to focus on the drug one night, I didn't really notice the euphoric effects. Lying on my bed in the dark having just consumed another line was very pleasant, almost serene; I initially found myself in this situation because lying on my back was the best way to stop my nose running.
I do have a small amount of the 'pseudoephedrine' precursor remaining, which I doubt I will be reducing. Though stimulants are undoubtedly useful for those lucky souls who can control their use, and can be very fun for those of us who can't, I feel my ability to do things I want to do is best achieved without the push of stimulants. I have wasted a fortune on making useless precursors which seemed so fantastically interesting only 3 days previously.
Both stimulants are still worth trying, but from my experience of it, methaephetamine isn't worth the hassle of making by this method. I would very much like to see whether the high doses of methaephetamine are typical for other users, or if the high doses I found necessary are because of cross tolerance between it and the keto analogue. The fact that both stimulants are legal worldwide - to the best of my knowledge - is, in my opinion, reason enough to make and try them at least once. It seems that 2-methylamino-1-phenyl-1-butanone is actually more potent than methaephetamine, in contrast to methamphetamine being more potent than methcathinone. Methaephetamine, however, gives a more clear-headed high than the keto analogue, and would be better suited for low doses as an aid to studying/cleaning.
What is more interesting is that the basis of this method has given me an idea for a synthesis with much greater scope than that of the original: a novel route to ring substituted PEAs/amphetamines based on the route above; that is, a total synthesis avoiding the use of benzaldehydes or nitroalkanes. How long this will take will, I suppose, depend how my motivation fares.
This aside, I'm all ears on any further information on the phenoxyethylamines/phenoxyisopropylamine
(Hive Bee)
02-07-04 14:12
No 487075
Kinetic, thanks for sharing the bioassay info. It is a very interesting read and a good addition to the otherwise poor bioassay reporting tradition on the Hive
.Otherwise I'm not directly interested in stimulants, but would like to boldly attempt some SAR generalization between the cathinones and the “serotoninergic” amphetamines. I know there is not much enthusiasm about ring-substituted cathinones, probably because nobody expects them to be psychedelic (not even me), but they might have some other virtues (for example, the betta-oxo-MDMA generalize with MDMA in animals Post 108548 (dormouse: "Methylenedioxy-cathinone analogs -Lone Deranger", Novel Discourse)). But I think you already know all this (Post 407144 (Kinetic: "And", Stimulants)). Therefore, I salute your idea of attempting a new route to ring-substituted amphetamines, especially because I expect you are also going to rapport on the effects of the cathinone intermediates
.Now, about the herbicides, I mean phenoxyisopropylamines, first thanks to Rhodium for the paper. Then I also think there is no need for an ‘agent orange’ panic, since nobody is gonna use chlorophenoles. Seams like the dioxane bastards form because having three chlorines on the phenol activate it for the aromatic nucleophilic substitutions. Two chlorines are probably not enough for that side reaction (but it is better to be sure and avoid chlorophenoles at all). My idea was to use p-MeO-phenol and chloroacetone as the starting materials and to brominate the resulting phenoxyisopropylamine, therefore yielding 3-Br-4-MeO-phenoxyisopropylamine or 2,5-diBr-4-MeO-phenoxyisopropylamine. If the active conformation at the receptor is like I imagine it to be the former should be a DOB analogue. The phenoxyethylamines are however out of my poor chem/equipment capabilities as I don’t have neither aziridine nor LiAlH4 (for the reduction of ArO-CH2-CONH2). Sadly, the phenoxyisopropylamines will also have to wait until I’ll have some more free time.
I couldn’t not note the phenomenal example of bioisosterism we have here. These herbicides are bioisosteric to 3-indolyl-acetic acid (a plant growth hormone) while the phenoxyisopropylamines should “substitute” for serotonine!
The conclusion that the x-chlorophenoxy group substitute for the indole rings in organisms so distinct like plants and animals is just amazing to me. If I would not be a chemist I would like to be a botanic
.
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
02-08-04 16:56
No 487311
(Rated as: good read)
Or
'Moderately Optimistic About Cathinones'
Firstly, thanks Nicodem for the interesting refs you have so far given on the phenoxyethylamines (POEAs?), and for the modifications to the alpha- side chain. You saved me some time and money as I had considered making alpha,alpha,alpha-trifluoromethamphetamine via reductive amination of the corresponding ketone, which I had hoped to make from the Grignard reaction between benzylmagnesiumbromide and trifluoroacetic anhydride.
Now to cathinones:
Because of their legal status and ease of preparation, I've tried a few cathinone analogues over the past 1.5 years. Although in general they have been somewhat of a disappointment, I still think some of them are worth trying. I have tried the following, in chronological order:
1-(4-methylphenyl)-2-(pyrrolidin-1-yl)-h
2-methylamino-1-phenyl-1-butanone
4-methylmethcathinone
4-fluoromethcathinone
4-methoxymethcathinone
Methylone
Alpha-pyrrolidinylpropiophenone
MPPH is highly active and rather potent (20-50mg recommended dose), but in me, the side effects of paranoia were too great. However this was the first drug I ever made, and knowing of the negative effects impurities can have on experiences, it would be unfair to blame the 'crash' and the paranoia on the drug itself, as they may have been in part due to my inexperience with the synthesis.
After multiple failures with the acylation of benzodioxole, I decided to try acylating toluene, which led to my discovery of 4-methyl methcathinone's effect. The bioassay can be found in Post 424046 (Kinetic: "Next morning...", Novel Discourse).
I wasn't particularly surprised to find 4-methoxymethcathinone inactive, but was rather more upset to discover 4-fluoromethcathinone was as good as inactive too. Until Bandil's recent thread which confirmed 4-fluoro-4-MAR didn't live up to his expectations (nor mine, as I made some by a different route and tested it just after him), I had worried that I may have actually tried 1-(4-fluorophenyl)-2-methylaminoethanone
After finally managing to acylate benzodioxole with a mixture of propionic acid/trifluoroacetic anhydride, I was disappointed by methylone itself, but I suspect this was due to my overly high expectations of it. I had hoped it would substitute for MDMA but in me it doesn't. Because of this I only made it the once, though I will try it again this summer in a different set and setting; last summer when I tried it I wasn't feeling too good about myself. Unlike on ecstasy, even with high doses of methylone taken in a nightclub, I couldn't completely lose the self consciousness which is so overwhelming in my everyday life. I suppose that's why I like ecstasy so much.
I didn't enjoy alpha-pyrrolidinylpropiophenone at all, though others I have spoken to have recommended it. Some of it's negative effects in me can be found in Post 449770 (Kinetic: "Yes", Newbee Forum).
I'm still interested in trying the N-unsubstituted methylone analogue, which I suppose could be made by treatment of MDP1P first by bromine and then by 1eq. sodium azide; the resulting azidoketone (which should be formed in almost quantitative yield, from experience) would be reduced to the aminoketone by either CTH or Zn/ammonium chloride. The use of azidoketones is also the basis for my proposed 'novel route to amphetamines'.
(Hive Bee)
02-10-04 17:29
No 487704
Kinetic, your limited bioassay based SAR of cathinones was a very precious gift and I’m still puzzled by some strange relations. I’ll try to analyze them as it might be of help for planning new potentially active cathinones and I hope some constructive criticism will follow. Let me first summarize these relations in two points, as I will use them later:
1. MPPH having a side chain 3 carbons longer than alpha-pyrrolidinylpropiophenone is almost of magnitude more potent and (if I understood well) qualitatively somewhat different. However at the same time 2-methylamino-1-phenyl-1-butanone does not follow this logic as is weaker than methcathinone (a bioassay of 2-pyrrolidinyl-1-phenyl-1-butanone could give more info on this).
2. The addition of a p-methyl does not abolish the activity of methcathinone, while a p-methoxy or p-fluoro have deleterious effects.
The first point indicates there are probably at least two mechanisms or sites of action for these cathinones to work in the brain (if we omit the effects of metabolism for now). One site can accommodate the long side chain while the other can’t. Speaking hypothetically, maybe the “short chain” aminopropiophenones act trough a similar mechanism like (meth)amphetamine releasing dopamine, while the “long chain” cathinones (like MPPH and partially aminobutirophhenones) act inhibiting its reuptake (or whatever else).
The second point is also interesting. Both an electrondonating (MeO) and an electronwithdrawing (F) group abolished activity, while the methyl being only poorly electron donating retained the activity. Off course, if there would be a SAR generalization with amphetamines it should be advisable to test the corresponding cathinones and not methcathinones, but there seams little to generalize in between these two types of compounds. The reason of both being inactive could be for two different reasons. Maybe the para position does not allow for any group less liphophylic than a methyl and at the same time does not allow any electronwithdrawing groups (in such case p-ethyl-C should retain some activity).
Both points considered together gave me the idea that one of the site of actions of the cathinones (especially the “long chain” ones) is the same as for the N-benzylpiperazine (BZP). This bold supposition is based first on (besides on both being stimulants) the comparable bulkiness of the side chain in BZP and MPPH and secondly that a similar pattern of the para substitutituion influence (point 2) can be applied for BZP as well. I found that p-methyl-BZP is more or less equipotent to BZP, the p-methoxy-BZP is inactive as a stimulant and only has a hint of anxiogenic activity above 300mg and the p-nitro-BZP was also not a stimulant (on turn it was “serotoninergic” above 50mg, but unfortunately not of the psychedelic kind). To bad I don’t know anything about p-flouro-BZP. The p-nitro-BZP was the only BZP with an electronwithdrawing group that I tested. However, it was found that p-chloro-BZP as well as p-nitro-BZP is a weak SERT inhibitor (Neurosci Lett, 1993, 152: 17-20).
Methylone seams to be again something else, probably acting on a “third cathinone site” that is seemingly located somewhere in the serotonine system. To bad we don’t know much about 4-X-2,5-dimethoxy-cathinones in vivo activity.
“The real drug-problem is that we need more and better drugs.” – J. Ott