Norbuprenorphine (also Acetorphine)

[Nagelfar]

Does Norbuprenorphine have a potency equivalent to Buprenorphine but just as a pure agonist (rather than mixed agonist/inverse-agonist)? or otherwise what are its pharmacological differences?

Also does anyone know a more potent morphinan/morphinium style opioid than Acetorphine? It, and its subvariety like (nor)buprenorphine have molecular branches on the opposite end from the active side (which molecular position number would that be? around the far side of the molecule from the 6 position) does this help in anchoring it when bound to the receptor or some such? As I know the opposite end is the side that actually binds to the mu receptor. Would different themes upon this type of conformation assist with potency in any way?

Norbuprenorphine:
http://en.wikipedia.org/wiki/File:Norbuprenorphine.png

Acetorphine:
http://en.wikipedia.org/wiki/File:Acetorphine.png

 

[dread]

Well, not sure about norbuprenorphine - most opioid agonists are tertiary amines. But if you add an N-methyl to it then yes it will be a full agonist.

 

[Nagelfar]

Also what is the Nor- suffix in molecule names from / does it mean? I notice it's mostly in metabolites but that may be from a natural human metabolic process (i.e. norpethidine, norcocaine, etc.)

 

[dread]

From German: Nitrogen Ohne Radikal. It basically means a compound with a functional group removed from a nitrogen.

For example you could say amphetamine = nor-methamphetamine.

Sometimes it is also incorrectly used to mean the removal of a functional group from any atom, ie. noribogaine which should properly be called O-desmethyl-ibogaine. O-desmethyl means removing a methyl from an oxygen atom. Ie. morphine would be O-desmethyl-codeine.

 

[Nagelfar]

Interesting dread, good to always learn something new here if you ask the right questions.

So does anybody have any input about Norbuprenorphine or Acetorphine?

 

[dread]

Norbuprenorphine is inactive or has very little activity (so little it can't be noticed). It is a metabolite of buprenorphine, first-pass metabolism converts buprenorphine very efficiently to norbuprenorphine so if you want to experience the lack of effects, just eat some buprenorphine.

 

[seep]

The Wiki skeletal formulas for etorphine and acetorphine seem to be wrong:

The vinyl bridge from carbon 6 to carbon 14 should be a cis-vinyl (I think), but the formula depicts a trans vinyl. The trans isomer seems impossibly strained.

 

[Nagelfar]

Norbuprenorphine is inactive or has very little activity (so little it can't be noticed). It is a metabolite of buprenorphine, first-pass metabolism converts buprenorphine very efficiently to norbuprenorphine so if you want to experience the lack of effects, just eat some buprenorphine.

The Wikipage said it was a full agonist and contributed to buprenorphine's effects. In fact are you just assuming that answer? The journal sources below state clearly: "norbuprenorphine is a potent opioid agonist"

QUOTE from Wikipedia article:

"''Norbuprenorphine acts as a μ-opioid, δ-opioid, and nociceptin receptor full agonist,[1][2] as well as a κ-opioid receptor partial agonist.[2] Norbuprenorphine crosses the blood-brain-barrier similarly to buprenorphine and likely contributes to its effects.[3]''"

References for above

[1] Yassen A, Kan J, Olofsen E, Suidgeest E, Dahan A, Danhof M (May 2007). "Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of norbuprenorphine in rats". The Journal of Pharmacology and Experimental Therapeutics 321 (2): 598–607. doi:10.1124/jpet.106.115972. PMID 17283225

[2] Huang P, Kehner GB, Cowan A, Liu-Chen LY (May 2001). "Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist". The Journal of Pharmacology and Experimental Therapeutics 297 (2): 688–95. PMID 11303059

[3] Jensen ML, Foster D, Upton R, Grant C, Martinez A, Somogyi A (April 2007). "Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model". Xenobiotica; the Fate of Foreign Compounds in Biological Systems 37 (4): 441–57. doi:10.1080/00498250701251126. PMID 17455115. http://informahealthcare.com/doi/abs/10.1080/00498250701251126

...

I just assumed it helped nudge bupe 's activity toward full agonist over mixed agonist/antagonist or some such as it metabolized (making it why it is possible to "withdraw" from buprenorphine to some extent.)

 

[dread]

Well this is the first time I've heard it described as a "potent" agonist.

The first-pass metabolism produces norbuprenorphine, and bupe is completely inactive orally. If the metabolite was a potent agonist, then you should be able to experience agonist type effects from eating buprenorphine. Clearly this is not the case.

 

[Nagelfar]

Well that's an interesting facet, this begs the question all the more that I'd find the answer intriguing. I do know that sometimes when speaking of particular prodrug functions things are called inactive completely by a route or all routes (heroin) but are potent because of their constituent metabolite by that route, etc.

 

[dread]

Well norbuprenorphine has no active metabolites AFAIK. The only route of metabolization IIRC is glucuronide conjugation which produces an inactive compound...

One possibility is that if all of the buprenorphine is not metabolized at once then the remaining buprenorphine keeps the norbuprenorphine from binding... But then, there should still be some oral activity from the buprenorphine.

Hmm, this is a puzzle.

 

[seep]

Actually, wikipedia has their structures completely bass-ackwards. Could somebody check these revisions against the IUPAC to see if they accurately represent etorphine & acetorphine? Thnx.

 

[amanitadine]

buprenorphine isnt completely inactive orally. Its bioavailability is just about a third of what it is when taken sublingually. (10% vs 30% +-).............

 

[laudium]

I read somewhere that norbuprenorphine is quite toxic compared to BUP. And I believe nor-BUP acts as a kappa agonist as well.

kappa agonist are no fun

As for why eating bup doesn't result into a full agonist effect is because of glucoronidation.

My understanding is that only like ~10% is transformed into BUP by CYP3A4, the removal of the methylcycpropyl. Then both BUP and nor-BUP are extensively conjugated with glucoronidation.

As far as orally taking BUP. I agree with the above poster. It has activity around 1/10th the parenteral. I have seen this first hand when a naive-opioid person accidentally swallowed the tablet.

Now if a methyl was attached to the N at the 17 position. Then you would likely have a very mu-potent chemical, and possibly still kappa- agonist.

There is no real way of getting bup to be a full mu agonist without affecting the other receptors, at least with body chemistry. A high from this chemical can only be achieved by paterental use and no opioid tolerance.

Its very potent to the non-tolerant

 

[laudium]

Seep the structure is correct on wikipedia. What are you talking about?

Look up Oripavine. Etorphine and bup are Bentley compounds.

You are talking about the double bond on the bridge right?

 

[seep]

^it's even wrong on pubchem. Use pubchem's 3D plugin and you'll see how you'll get something entirely different

(keeping in mind that skeletal formulas have to be unambiguous to machines, not just to humans)

 

[Hammilton]

norbuprenorphine is definitely active.

there are actually quite a few nor-opioids ie: n-desalkyl derivatives and metabolites, secondary amines, which are as potent or more potent than their tertiary amine counterparts. Morphiquet commented on this once and I might have it backwards. the secondary amines either generally have higher efficacy or higher potency, in general. Maybe it's efficacy, because obviously efficacy increases from bupe to norbupe as it goes from partial agonist to full agonist. perhaps it's potency that drops quite a bit.

 

[MurphyClox]

The Wiki skeletal formulas for etorphine and acetorphine seem to be wrong

The vinyl bridge from carbon 6 to carbon 14 should be a cis-vinyl (I think), but the formula depicts a trans vinyl. The trans isomer seems impossibly strained.

The structures are actually correct; the double-bond can only exist cis-configured, because it is fixed in the ring-system. The way it is depicted at Wiki and PubChem was solely chosen because it is not possible to draw it otherwise. The bonds from both C6 and C14 go back behind the projection plane, which results correctly in the cis-configuration, as expected:




The trans-configuration would look like this:



...and can only be drawn in 2D; trans-configuration would imply that the double-bond goes right through the C-ring, which is not possible.


Peace! - Murphy

 

[seep]

This has given me a headache, but I'll try to demonstrate how we can't possibly be talking about the same molecule.

Here's an extremely crowded screenshot of pubchem's 3D interpretation of etorphine:

I froze it that way to preserve the relative positions of the phenolic ring (top left) and the ethereal ring (middle left). When we bring the other ether (the terminal one) towards the bottom left, you see that:

• The vinyl bridge projects out of the page
• The amine bridge projects into the page

Now compare to the wiki skeleton:

You see that the phenol and the ethers have the same alignment, but the orientation of the vinyl bridge and the amine bridge have inverted.

It is impossible for those to be the same molecule. Side by side you can see this:

NSFW:

 

[MurphyClox]

I see what you mean, but PubChem's implemented 3D-viewer is simply misinterpreting the stereochemistry of the 2D-structure. When I prepared the pictures for my last post (...ChemDraw for 2D, then Chem3D for 3D, then MM2 in the same program), I needed to arrange some residues manually first, before the force energy minimization be applied, because Chem3D had some difficulties with interpreting the configuration right, too.

Lesson learned: Don't let computer programs do the whole work for you! They are only as good as the person who uses them. The stereochemistry in the (2D)-Wiki-picture is definitely correct: Ethylene-bridge is sticking behind the projection plane, the piperidine-ring is coming to the front.


- Murphy