Nucleoside derivatives as sedatives

[polymath]

I was looking for alkylurea derivatives with sedative effects with Google (see Hammiltons bromisoval thread), when I found some articles about uridine derivatives that have hypnotic action...

The potent depressant effects of N3-phenacyluridine in mice.
Biol Pharm Bull. 1994 Apr;17(4):514-6.

The hypnotic activity of N3-phenacyluridine in 2.0 mumol/mouse by intracerebroventricular (i.c.v.) injection was 20 times stronger than that of known N3-benzyluridine. In 0.5 mumol/mouse, i.c.v., this compound strongly potentiated both pentobarbital- and diazepam-induced sleep as compared to N3-substituted uridines, including N3-benzyluridine. Furthermore, the compound caused motor incoordination as well as decreasing spontaneous activity in the same dose. These results indicate that among the N3-substituted uridines and related compounds previously reported, N3-phenacyluridine possesses potent depressant effects.

In other papers about this subject it is claimed that compounds like phenacyluridine and benzyluridine are also active after intraperitoneal injection, but nothing is said about oral administration.

There's a hypothesis that the nucleoside derivatives exert their sedative action through some new unknown receptor, see http://www.journalsleep.org/Articles/240301.pdf .

So, apparently these compounds are hypnotics and also cause other signs of intoxication (motor incoordination). What makes this interesting is that things like benzyluridine would be easy to make from commercially available uridine by first protecting the hydroxyl groups by esterification and then reacting the ester with an appropriate electrophile. Of course these compounds are not necessarily 'recreational', a huge i.m. dose of haloperidol would probably cause sedation and motor incoordination too, without being fun in any way. No one has tested whether animals self-administer the nucleoside sedatives...

Is it likely that these compounds would be active orally, or would they be destroyed by first-pass metabolism?


Structure of phenacyluridine:

 

[Black]

it would be broken down by the enzymes in the intestine, so oral application is most certainly out.

 

[polymath]

it would be broken down by the enzymes in the intestine, so oral application is most certainly out.

That was what first came to my mind...

I read some papers about the use of uridine itself as a pharmacotherapy of bipolar disorder, and it seems to have an oral BA of only 8%. Apparently triacetyluridine, where the hydroxyl groups in the carbohydrate part of the molecule have been esterified, has a much higher BA.

 

[Epsilon Alpha]

I was shocked to find that this wasn't about adinosine analogs, there's a ton of well known depressants that block its reuptake or agonize the receptor directly. Any idea what causes the effects with these particular pyrimidine analogs?
http://en.wikipedia.org/wiki/Adenosine_reuptake_inhibitor

We found the specific [3H]N3-phenacyluridine binding in synaptic membranes of mice, rats, and bovines, and the binding site was widely distributed in the striatum, thalamus, cerebral cortex, and cerebellum.47,48 From these results, [3H]N3-phenacyluridine binding site was proposed as an "uridine receptor," which may play an important role in the CNS depressant effects of oxopyrimidine nucleosides. Recently, purine receptors were well established by many investigators, and mainly divided into two family of purine receptors (i.e., adenosine/P1 receptors and P2 receptor.)57 However, there is only indirect evidence of P2Y receptor because of lack of the specific ligands for the receptor.
Since the P2Y receptors have a affinity to uridine triphosphate,57-59 contribution of oxopyrimidine nucleoside derivatives to the receptor was also speculated. We revealed that N3-phenacyluridine was biotransformed to N3-(S)-(+)-α-hydroxy-β-phenethyluridine in mice as an active
metabolite.54 The N3-(S)-(+)-α-hydroxy-β-phenethyluridine exhibited hypnotic activity and synergistic effects with barbiturates by i.c.v. injection in mice. Displacement ability of specific [3H]N3-phenacyluridine binding to synaptic membranes of thebovine thalamus by N3-(S)-(+)-α-hydroxy-β-phenethyluridine was higher than that of the (R)-(-)-isomer. Since these enantiomers have different pharmacological potency and binding affinity to the binding site, the results may account for the mechanism of action of oxopyrimidine nucleosides in the CNS depressant activity, especially the hypnotic activity.

Very interesting, so there is a potential uridine receptor with potent sedative effects. If I wasn't so worried that this would cause reverse transcriptase inhibitor type side effects and cancer I'd be more interested though lol.\

Here's some reading on the P2Y2 receptor which is suspected to be one of the targets it acts through:
http://www.ncbi.nlm.nih.gov/pubmed/21401495
http://www.ncbi.nlm.nih.gov/pubmed/23117439
http://www.ncbi.nlm.nih.gov/pubmed/22528682
http://www.ncbi.nlm.nih.gov/pubmed/22467178

 

[Epsilon Alpha]

Polymath, do you have any additional studies on this target?

 

[polymath]

I didn't find much more... All the studies about this subject seem to be made by the same Japanese researchers, so there's no independent confirmation of the results.

Phenacylthymidine seems to have sedative effects, too: http://www.ncbi.nlm.nih.gov/pubmed/8820928