Activity of 3 / 6 & 3,6 position iterations of morphine derivatives and metabolites.

[Nagelfar]

Activity of 3 / 6 & 3,6 position iterations of morphine derivatives and metabolites.

My main question is mostly this: why are 'morphine-6-glucuronide' & 'morphine-3-glucuronide' considered active, as morphine-3,6-diglucuronide is considered inactive; while 6-acetylmorphine is considered active; but 3-acetylmorphine & 3,6 diacetylmorphine are both inactive. The former instance, the metabolites, imply that either one position, the three or six, alone have to be open for binding and agonism to function; however the second instance, the acetyl-ester-prodrug, implies that only the 6 positon functions for any agonism.... Is there a reason it appears this way?

 

[mad_scientist]

Morphine-3-glucuronide is not active, e.g. see PMID 19351545

"This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G."

The 3-OH should be exposed for optimum activity and while this is not always required, compounds with free 3-OH are always more potent than when the OH is masked as an ester or ether.

 

[Nagelfar]

Morphine-3-glucuronide is not active.

Well there's my problem... (*uses google to cite / edits & sources wikipedia article*)

 

[Hammilton]

I've always been surprised that m6g is as potent as it is. Does m6g actually bind or is it purely a prodrug?

 

[Nagelfar]

I've always been surprised that m6g is as potent as it is. Does m6g actually bind or is it purely a prodrug?

What would it be a pro-drug to? Does it break back down into morphine...? ;/

 

[flacky]

If I may tack on to this, I wonder if M6G binds to the same subreceptor that 6-MAM has been shown to bind to (exclusively?)