Normorphine?

[Sphinx (Afterlife)]

Wuts this? A metabolite of Morphine or sumthing?

Is it more potent than morphine? I read somewhere I forget that was comparing a new drug to Normorphine and Morphine and stated it was 10x potency of Normorphine and 100x that of Morphine, so would that mean that Normorphine is stronger than Morphine analgesicly by 10x (respectively, of course)?

 

[BilZ0r]

It should be a CYP3A4 mediated morphine metabolite, if all things a fair in good in the world (the opioids usually are active through CYP2D6, and are inactive and start with NOR, through CYP3A4, I believe morphine goes to dihydromorphinone (CYP2D6) and normorphine (CYP3A4)).

Anyway, according to the PDSP and a paper cited as Pert et al., 1974; normorphine has a mu opioid receptor affinity of 700 and 15nM (with/without NaCl), while morphine has a Mu opioid affinity around 1-5nM (Pert et al., 1974 reports 3 and 110nM with/without NaCl respectivity).

 

[fastandbulbous]

I believe morphine goes to dihydromorphinone (CYP2D6)

I thought 2D6 was responsible for O-demethylation of the 3-position (codeine -> morphine), not rearrangement of the double bond at the 7,8 position to 6,7 (with subsequent conversion to stable keto-enol tautomer, dihydromorphone); after all, hydromorphone is a hell of a lot more active at the mu receptor than morphine.

As far as I was aware, morphine mostly ends up as normorphine & morphine-6-glucuronide

 

[BilZ0r]

Maybe I'm wrong about the dihydromorphinone bit... what does CYP2D6 do to morphine then?

 

[fastandbulbous]

Didn't think it did anything, I thought it was just codeine, DHC (3-O-alkylated compounds) etc that it metabolized (O-dealkylation)

 

[Riemann Zeta]

I didn't think nor-morphine was active at all. The OP might be thinking of the extremely rare opioid Numorphan, which is 6,7-dihydro-oxymorphinone (oxymorphone)--a metabolite of oxycodone with at least 10x the potency of morphine.

 

[paradoxcycle]

Didn't think it did anything, I thought it was just codeine, DHC (3-O-alkylated compounds) etc that it metabolized (O-dealkylation)

The CYP450 2D6 isozyme is responsible for 0-demethylation of codeine into morphine (codeine is just the methyl ether of morphine), or analogously, hydrocodone into hydromorphorne, or oxycodone into oxymorphone.)

 

[who mE?]

Opioid N-substituants

Normorphine is N-demethylated morphine... it is 50% of the potency of morphine according to the book Opioid Analgesics - Chemistry and Receptors, by Casy and Parfitt.

Interestingly enough, according to my memory nearly all 5-ring (and many 4-ring) N-methylated opioids are about 2 times as potent (by mass) as their N-demethylated counterparts. So for example, nor-codeine is 50% as potent as codeine, and nor-oxycodone is 50% as potent as oxycodone. Another "Rule of thumb" for opiates is that when an allyl group is attached to the N, it becomes an antagonist, which will usually be active at a much lower dose than the original substance. To offer one more example of a pattern between structure and activity to pique your interest, if an opiate has a (2-phenyl)-ethyl substituant on the amine, it will be potentiated to somewhere between 20 and 100 times the potency of the usual N-methyl opioid.

This reminds me of an old thread on the deceased "The Hive" board where posters from countries where Naltrexone is available OTC were trying to figure out how to strip off the allyl group from Naltrexone to get nor-oxymorphone. With 50mg per naltrexone pill, and boxes containing 60 (2 months), this would yield a lot of nor-oxymorphone in theory. Its a nice thought considering how most other uses of naltrexone are either unintentionally or intentionally sadistic and ineffective.

I have a collection of references available here: http://hive.dopers.org/N-substituants.txt

 

[Smyth]

^Yeah but those ones are quite easy to spot.

SAR's can get appreciably more complex than this though.

Also you didnt mention the N-cyclopropylmethyl used in mixed (ant)agonists (eg. bupe http://en.wikipedia.org/wiki/Buprenorphine).

In light of your generalizations, may I ask u to consider what N-PE etorphine would be like? (im only joking)