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HU-210, novel NMDA structure?

Sturnam

Sturnam

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Aug 12, 2008
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I was looking on wiki at HU-210, and it mentioned that the (-) enantiomer was an NMDA antagonist. I confirmed this with a pubmed search.

My question is....huh? I'm not good with 3-D overlays, but as far as I can tell, this is far from any known NMDA antagonist. Do you think this could be a starting point for novel NMDA antagonist compounds? Any idea how it conforms to be an NMDA antagonist? I know that this will probably be unanswered, but just curious if anyone knows the answer.

Also, does anyone think that NMDA antagonism could have some special synergy with CB1/2 agonism? Maybe as a treatment for neurodegenerative diseases for pain/inflammation (CB1/2 activity) as well as slowing symptoms (NMDA antagonism)?

Any other thoughts on this?
 
1.) Could we see please the respective citations from PubMed?

2.a) (maybe already answered by 1.) Is the binding site at the NMDA-receptor known for (-)HU-210?

2.b) How potent is (-)-HU-210 as NMDA-antagonist?


Peace! - Murphy
 
...well, OK, found it faster than expected. Answer to 1.):


Howlett AC, Champion TM, Wilken GH, Mechoulam R.
"Stereochemical effects of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor."
Neuropharmacology 1990, 29(2), pp.161-5.
Abstract
The recent preparation of the enantiomers of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (THC-DMH), recrystallized to absolute enantiomeric purity, has made it possible to examine the requirement for stereospecificity for the interaction of this component with the cannabinoid receptor, defined by the binding of [3H]CP-55,940 and the adenylate cyclase enzyme. The enantiomer (-)11-OH-delta 8-THC-DMH exhibited a fully efficacious and potent (IC50 = 1.8 nM) inhibition of the accumulation of cAMP in intact N18TG2 cells. The (-)enantiomer was as efficacious and potent (Kinh = 7.2 nM) as desacetyllevonantradol in inhibiting adenylate cyclase activity in membrane preparations. The (-)enantiomer was able to compete fully for the specific binding of [3H]CP-55,940 to membranes from the brain of the rat in homologous displacement studies (Ki = 234 pM). The potency ratios exhibited by the (-) to (+)enantiomers of 11-OH-delta 8-THC-DMH exceeded 1000 for each of these activities.
Click to expand...


Darlington CL.
"Dexanabinol: a novel cannabinoid with neuroprotective properties."
IDrugs 2003, 6(10), pp.976-9.
Abstract
Dexanabinol was developed as a synthetic analog of the cannabinoid tetrahydrocannabinol, however, the action of the drug is as a weak, uncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor. Dexanabinol is an effective neuroprotectant in animal models of hypoxemia/ischemia, neurotoxin exposure and nerve crush. Unlike some other uncompetitive NMDA receptor antagonists, dexanabinol does not produce psychotrophic effects and is generally well tolerated in humans. In this respect it is similar to the uncompetitive NMDA receptor antagonist memantine. Dexanabinol is currently in phase III clinical trials for severe head injury. It is a promising drug that appears to be able to provide the therapeutic benefits of uncompetitive NMDA-receptor antagonists without the adverse side effects associated with some of the earlier drugs of this type.
Click to expand...
 
MurphyClox said:
2.a) (maybe already answered by 1.) Is the binding site at the NMDA-receptor known for (-)HU-210?

2.b) How potent is (-)-HU-210 as NMDA-antagonist?


Peace! - Murphy
Click to expand...

Answer to 2.a) not completely sure, but for some reason I want to say it's on the extracellular side, and not in the Mg2+ channel. Maybe by the glycine site somewhere? I'll check when I have more time.

Answer to 2.b) I believe they said it was pretty weak. It's also an uncompetitive antagonist. But nevertheless, a starting point.

Ketamine/Tiletamine/PCP/etc are noncompetitive antagonists right?
They block the Mg2+ pore regardless of whether the agonist is bound, correct?

This seems like a good medicine, if the glutamate overactivity theory is correct. It would block high levels of glutamate activity, but leave relatively low levels normal due to its uncompetitive antagonism.
 
There are really numerous other weak ligands for the NMDA-receptor known. Therefore, I wouldn't consider this as a good starting point. A lead structure in this case should show at least something in the one-digit-mM-range or below, otherwise the way to go is faaaaar too long IMHO.


Peace! - Murphy
 
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