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Mephedrone science

Does sympathomimetic platelet activation have something to do with ppa hemorrhagic stroke ?
 
vecktor said:
Does anyone know anything about stimulant induced/ sympathomimetic platelet activation? it appears to work through adrenergic receptors and leads to increased clotting.

It is reported for several betahydroxyphenethylamines like ephedrine and phenylpropanolamine, I wonder if mephedrone blue knees have anything to do with ??

If anyone knows how platelet activation happens and the toxic symptoms it causes I'd like to hear it.
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Maybe you'd like to start with this review:


"Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo."
Eur J Haematol 2000, 65, pp.357-369
Abstract
Overactivity of the sympathetic nervous system (SNS) has been related to increased cardiovascular morbidity. Historical reports suggest hastening of blood coagulation following intravenous administration of epinephrine. Given the important role of the hemostatic system in atherosclerosis and thrombosis, it is surprising that short-term adrenergic effects on blood coagulation, fibrinolysis and platelet activity have not been scrutinized closely. To elucidate such effects in vivo, this paper reviews human studies in which a- and b-sympathomimetic agents had been infused. The literature suggests a dose-dependent stimulation of factor VIII clotting activity, von Willebrand factor antigen, tissuetype plasminogen activator, and platelets within a 15- to 40-min infusion of epinephrine. Precise mechanisms underlying hemostatic changes with sympathetic activation remain to some extent speculative. However, there is evidence from adrenoreceptor blockade studies that coagulation and fibrinolysis molecules are released into circulation by stimulation of vascular endothelial b-adrenoreceptors (most likely b2-receptors). Combined a2- and b2-adrenoreceptor-related mechanism(s) are responsible for platelet activation. Short-term activation of the SNS effects regular hemostatic activity. While in healthy individuals the hemostatic balance between coagulation and ®brinolysis may be preserved, catecholamine surge may trigger a hypercoagulable state and enhance the odds of overt thrombosis in patients with atherosclerotic disease.
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Look in particular at Table 1, which summarizes impressively the major impact of adrenergic substances on hemostatis; several entries mention action on platelets!

Full article: http://img682.imageshack.us/i/eurjhaematol200065p357.pdf/


Another article that seems to provide further insight is Clin Sci 1986, 70(2), pp.147-53, but unfortunately there is no online-version available of that year. Take the abstract instead:

"Desensitization of platelet alpha 2-adrenoceptors after short term infusions of adrenoceptor agonist in man."
The effect of intravenous infusion of catecholamines and related drugs on human platelet alpha 2-adrenoceptor number and function was investigated. Short (60-120 min) infusions of catecholamines with alpha 2 agonist activity in vivo produced attenuation of the platelet responses to adrenaline in vitro. This desensitization was specific for the adrenaline induced aggregatory response. The maximum number of [3H]yohimbine binding sites on platelets was not altered by adrenaline infusion. The ability of adrenaline to reduce platelet cyclic AMP levels was significantly reduced after the infusions. Acute infusions of alpha 2-adrenoceptor agonists may alter the coupling of the platelet alpha 2-adrenoceptor to adenylate cyclase.
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- Murphy
 
As an ignorant non-scientist, are the above posts saying this toxicity is not just limited to meph, but would also be an effect for 3-FMC and Methylone?
 
^I think they apply to all stimulants with sufficient peripheral activity. The PEA-family is not really selevtive in this respect.
 
mephedrone science

According to "Metabolism of the new designer drug mephedrone and toxicology" by Meyer, Peters, and Mauer, Ann Toxicology Anal. 2009 21S(1), mephedrone is "N-demethylated to the primary amine, the keto moiety is reduced to the corresponding alcohol, and the tolyl moiety is oxidized to the corresponding alcohol, aldehyde and carboxylic acid."
 
Rectify said:
According to "Metabolism of the new designer drug mephedrone and toxicology" by Meyer, Peters, and Mauer, Ann Toxicology Anal. 2009 21S(1), mephedrone is "N-demethylated to the primary amine, the keto moiety is reduced to the corresponding alcohol, and the tolyl moiety is oxidized to the corresponding alcohol, aldehyde and carboxylic acid."
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there is an echo in here see post #3 in this thread.....8)
 
Does someone know the melting point of pure 4-MMC hydrochloride?
Or can someone measure the mp of 4-MMC from vendors (optimally from more than one vendor)?

I'm asking myself whether the chinese-produced commercial 4-MMC is always pure. Measuring the mp of a substance is a good easy way to find out whether it is pure or not.
 
Secale, it doesn't necessarily have to be known. It's probably more important whether or not it melts in a broad range or narrow range. The narrower the melting range, generally, the purer the substance may be. It's still nice to know the melting point for sure, but this is a good way to get around that.
 
As requested by vecktor.

eims4mmc.jpg



eims4mmcpfpaderiv.jpg



vpir4mmc.jpg
 
vecktor said:
It does occur but I believe it is a minor pathway with pyrrolidine compounds:
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Does this imply that some pyrrolidine stimulants might mostly be substituted cathinone or ephedrine prodrugs?
 
thanks phase dancer for the spectra. :)

the spectra of methamphetamine is very close explaining some gcms misidentifications of mephedrone as methamphetamine, if the analyst doesn't scan below m/z 40 and uses certain commercial search software it gets a rather good hit using 58 and 91

cbook.cgi
 
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Quick question here, so last night me and a few buddy's polished off quite a bit of 4MMC, and it suddenly hit me:

4MMC has a relatively short half life, and a primary (nasty) metabolite which crops up in significant quantities.

Could increasing peak duration and reducing negative after effects be as simple as targeting the enzyme responsible for the production of 4-methylephedrine and inhibiting it?

Does anyone know how 4MMC is metabolized to 4-methylephedrine? If it's something in the CYP450, this should be relatively easy and effective...
 
You'd be looking for a benzylic ketone oxidoreductase, I'm not sure that'd be a member of the P450 family since they generally just makes alcohols out of alkanes or aryl rings (of course there are a million exceptions as P450 is enormous and there are new members discovered every day).
 
Vecktor from eveything i've read i completely agree with your point in post 8 that there is a really good chance of some serious neurological damage from mephedrone use.

I was curious if you had any ideas of where research to find out about any neurotoxicity should start?

From everything I've read it seems like even what specific transmitters are acting haven't been identified and most people are just assuming some DA and 5-HT actions. Based on the trip reports some DA activity in the A10, and probably some 5-HT 2A activity seems likely, but obviously we can't know for sure until some research is done.

I'm just an undergraduate behavioral neuroscience major, (trying to keep up with the discussion) but this is something that has really caught my attention because of how widely this substance is being used when people have no clue what it is really doing.

Sorry if this isn't the type of post you were looking for but I'm really curious as to how someone would go about starting to figure out the neurotoxicity.
 
Just search for amphetamine/substituted amphetamine neurotoxicity studies and see what they did in their methodology. Usually it involves analyzing neurotransmitter levels/neurotransmitter metabolite levels/other metabolic changes or staining neurons
 
Should be a snap to run meph through the same assays used for mdma, with some minor modifications perhaps.
 
Secale_Cornutum said:
Does someone know the melting point of pure 4-MMC hydrochloride?
Or can someone measure the mp of 4-MMC from vendors (optimally from more than one vendor)?

I'm asking myself whether the chinese-produced commercial 4-MMC is always pure. Measuring the mp of a substance is a good easy way to find out whether it is pure or not.
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I've measured the melting point of 4-MMC from three different vendors. All were white, mildly crystalline powders.

All three browned slightly from 201-203 C, which was followed by melting between 224 and 226 C.

What still irks me is that all of the reference information that Google turns up for melting point is all over the place, so hopefully this helps!

Edit: Tested another sample today. Very fluffy and crystalline. Browned at 218-220 C and melted between 230 and 232 C.
 
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