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Structure-minimzed THC derivatives

wungchow said:
the two methyl groups on the side chain, when it is long, probably helps twist it into the correct conformation in the lipid membrane (which is its binding domain)
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NCC's like CP 55940 are bound to one of the extracellular helices with hydrogen bonding from the norther OH playing a part, certainly mutation studies seem to indicate this is the case. There is also strong evidence that the non-classical bicyclic cannabinoids and the benzopyran classical cannabinoids bind in different locations with CP55940 binding to a mostly extracellular area of the receptor, but have somewhat overlapping binding sites with the benzopyran CBs. the WIN 55212 site is further in and I expect it does not require hydrogen bonding. mix n match SAR from bicyclic NCC's to benzopyran cannabinoids doesn't always hold true.
there are some good (free) papers at Kennisaw state University.. not going to link from here.
The whole thing is finally getting interesting with a huge amount of research going the field, CB1 agonists with limited CNS penetration, non competitive antagonists, inverse agonists, etc etc.

Some of the more potent cannabinoids especially some of Mechoulam's HU series also act as NMDA antagonists, the neuro protective and promoting effects of HU 211 perhaps rely more on NMDA antagonism than its CB activity.
At some point I must get a copy of Roger Pertwee's book 'the cannabinoids'

nolandin ether is very interesting, does anyone know if it requires a FAAH inhibitor to make it active in vivo?... FAAH inhibitors look a bit non selective and scary. Especially as lots have alkylating groups on them which is how they work. I think a couple of related compounds are used in industry as high pressure lubricants or something similar.

There appears to be a bit of a mess with defining things as partial agonists or full agonists at CB1 or CB2, what do you measure? some use the effect on potassium channels, or cAMP, or inhibition of mouse vas deferns contraction, often they define the most common CB agonist CP 55940 as a full agonist and go from there even though it may not be a full agonist either (there are other things with higher intrinsic activity than 55940 fuller than full almost). so it is rather difficult to compare results across different studies. so far it seems that HU 210 is the most potent substance both in terms of how well it binds to CB1 and CB2 and also has very high activity as an agonist.

Perhaps the ratio between relative CB1 CB2 agonism is the most useful indication for THC like effects but also the hardest to determine?
 
Is that the only possible means of death by canninoids? I mean, the cannabinoid system isn't very well understood, and with full agonists not being publically available like THC is, there could be other problems caused both long and short term.

But someone on my way home apparently gave me a cannabis sheet cake, which I ate completely as I walked- and here I am. Something like that? This is probably the stupidest post I've ever put here, so I apologise in advance :)
 
mad_scientist said:
New Analogs of Tetrahydrocannabinol. XIX
Roger Adams, Morton Harfenist, and S. Loewe
J. Am. Chem. Soc.; 1949; 71(5) pp 1624 - 1628
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Is that correct 1949? it must have been the university of Minnesota work from way way back.. I think he probably synthesised delta 9 before Mechoulam in the mid1960's, but didn't identify the correct isomer as the naturally occurring one.
 
I am not sure if Noladin ether is a FAAH substrate, but here is a path of inactivation...though i think i had something on that somewhere and it is not to a signifcant degree and is inactivated by other means such as Monoglycerol lipase


Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues

Authors:
Fezza F., Bisogno T., Minassi A., Appendino G., Mechoulam R., Di Marzo V.
Journal:
Febs Lett., 513, 294-298, 2002
Abstract:
The occurrence of the novel proposed endocannabinoid, noladin ether (2- arachidonyl glyceryl ether, 2-AGE) in various rat organs and brain regions, and its inactivation by intact C6 glioma cells, were studied. 2- AGE was measured by isotope dilution liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry, with a detection limit of 100 fmol. A compound with the same mass and chromatographic/chemical properties as 2-AGE was found in whole brain, with the highest amounts in the thalamus and hippocampus. Synthetic [(3)H]2-AGE was inactivated by intact rat C6 glioma cells by a time- and temperature-dependent process consisting of cellular uptake and partial incorporation into phospholipids. Further data suggested that 2-AGE is taken up by cells via the anandamide/2-arachidonoyl glycerol (2-AG) membrane transporter(s), and biosynthesized in a different way as compared to 2-AG.
 
vecktor said:
nolandin ether
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Haha excellent typo. We're so high there's nolandin! :D

I did find this about noladin ether:

USE/STABILITY: Stable for at least 6 months after receipt when stored at -80°C. We do not recommend storing the aqueous solution for more than one day.

Looks like it is probably a bit too unstable?

I'd post the source but its a supplier for the stuff so I can't.
 
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It says to keep in water for less than a day. I randomly searched through a whole lot of chemicals and drugs, and none of them had suggestions like -80C. A little ridiculous.

But that's not the only CB1 agonist that's not very stable at room temp.
 
yea but even if you keep it on dry ice full time, it may only last a year? thats shitty, both to buy the dry ice if you dont have the equipment, and that your drug would fall apart anyway.
 
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