ACEA, a new cannabinoid

[Hexagon Sun]

Pretty similar to anandamide.

There are some papers published but too dark/technical for me. Anyone could speculate about dose, duration and effects?

 

[MurphyClox]

1. This compound is a potential alkylating agent. I wouldn't touch it.

2. Because the only difference between "ACEA" and anandamide is the chlorine, I'd think that it is not active due to quick metabolic deactivation.

- Murphy

 

[Pomzazed]

Chlorine there looks bad indeed, seems like its gonna be covalently bonded to the receptor :S
(ie, stick to the receptor permanently until the body repair it)

 

[wungchow]

I wouldn't touch it with a 37.5 foot pole.

 

[dread]

I wouldn't touch the 40 foot pole that has touched the 10 foot pole that has touched this stuff...

 

[Black]

1. This compound is a potential alkylating agent. I wouldn't touch it.

2. Because the only difference between "ACEA" and anandamide is the chlorine, I'd think that it is not active due to quick metabolic deactivation.

- Murphy

the chlorine atom there could make it an unsuitable substrate for FAAH so it could well be active as well as maybe inhibiting the enzyme and therefore indirectly increasing anandamide concentration.

still with an alkylic chlorine it's not in any way suitable for human consumption.

 

[Hexagon Sun]

However, there are some abstracts claiming the compound as neuroprotective:

The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.

3,4-Methylenedioxymethamphetamine (MDMA) and fenfluramine are amphetamine analogues that both cause long-term depletion of serotonin (5-HT) and 5-HT uptake sites in brain tissue. Depletion caused by these amphetamines is commonly measured by labeling 5-HT uptake sites using 3H-paroxetine combined with autoradiography or, alternatively measuring the concentration of 5-HT in tissue using high-performance liquid chromatography (HPLC). A close correlation between the 5-HT concentration measured in micropunch samples and the density of 3H-paroxetine-labeled 5-HT uptake sites measured in corresponding 20 micron coronal slices was determined (R2 = 0.92). These methods combined demonstrated that the glycine-site specific NMDA antagonist ACEA 1021 (4 x 30 mg/kg, i.p., 2 hourly) given 30 minutes before (S)-MDMA (4 x 10 mg/kg, i.p., 2 hourly) was able to prevent the depletion of both 5-HT content and uptake site density but unable to prevent the depletion of 5-HT content and uptake site density caused dexfenfluramine (4 x 15 mg/kg, i.p., 2 hourly).

 

[MurphyClox]

Naaaaaahhhh!!!!!

ACEA and ACEA 1021 are not the same!

ACEA = N-arachidonoyl-2-chloroethylamine; mode of action: CB-agonist
ACEA 1021 = 5-nitro-6,7-dichloro-1,4-dihydroquinoxaline-2,3-dione, mode of action: NMDA-antagonist (glycine site)

For the latter, see e.g. Molecular Pharmacology 1995, 47(3), pp.568-581. And btw, this was written in the abstracts that you cited above! Did you actually read them or was it just a copy/paste kinda action?

- Murphy

 

[Hexagon Sun]

I did a quicky sheety read...

 

[Repulse]

What's that Chlorine molecule doing there.. eww.

Anandamide analogues are quite fascinating, though.

 

[any major dude]

^ I think they could have potential as antidepressants. Not this one though Since drug companies can't patent things that exist in nature, they have to mess with naturally occuring CB1 agonists significantly enough to patent them in order to keep their profit margin in line with their executives standards of living :/

Side note, how was marinol patented? Does it have something to do with the sesame oil solution or the synthesis method? Ugh... Patent law and profit motive in medicine.....

 

[Ne0]

Chlorine there looks bad indeed, seems like its gonna be covalently bonded to the receptor :S
(ie, stick to the receptor permanently until the body repair it)

So it makes me stoned for long periods?

 

[MurphyClox]

So it makes me stoned for long periods?

No. Upon covalent binding, the physiological response (i.e. the feeling of being stoned) doesn't last that much longer than with non-covalently binding ligands for several reasons. E.g.: Receptor downregulation, receptor internalization (followed by metabolization).
In the medium- to long-term, covalently binding ligands are a total desaster for the homeostasis of the brain's neurotransmitter storages resp. signaling networks.

As final note: Who says that it is just the CB1-receptor that can get alkylated? Although the probability may be higher due to the binding event (good positioning into a narrow pocket = higher probability of finding a suitable binding partner), molecules like ACEA can in principle anything in their way. Not good!

- Murphy