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Oripavine derivatives inclusive of a substitution at the 14-position (morphinans)

Nagelfar

Nagelfar

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Bridged_oripavine_general.png


Apparently 'isopentyl' at the "R" character on the above 2D image of a bridged oripavine derivative of the morphinan mu-agonist is 9,000+ x the potency of morphine. Taking the 14- substitution in PPOM (14-Phenylpropoxymetopon), alone, makes the latter "thousands" of time more potent than morphine. Would it multiply the isopentyl oripavine derivative the same (and could such be acetylated too like acetorphine is to etorphine as a oripavine in addition to it being the isopentyl at that 'R' site without losing the optimized affinity?) Also would these theoretically affect the binding of either or as an agonist? Could more be added like an azide group at the 6 position (like in azidomorphine) or a hydrazone as in the morphazones? What else could be done to make a morphinan have potency to put the fentanyl analogues to shame? (Which is basically my goal here)

Could someone draw an optimized 2D molecule that could be workable (exist without SAR impasse via entering through the realm of impossible physics which I am ignorant of) according to those main tenets I have posited above?
 
Could someone draw an optimized 2D molecule that could be workable (exist without SAR impasse via entering through the realm of impossible physics which I am ignorant of) according to those main tenets I have posited above?
Click to expand...

what?
 
Seems kind of obvious. Of course you can't have a 14 substitution on a bridged oripavine derivative. You'd need a pentavalent carbon. might be possible in some unique situation, but not here.

edit: I guess that's assuming that on these the 14 position is the same as in compounds like metopon (14-methoxymetopon is the only one I can think of off hand with a 14 substitution)
 
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OK, so lets simplify the question at this point in the thread for just now to what would be the working means making a (beneficial-to-the-mode-of-action) 14 position addition or replacement that could exist with some type of bridged substitution division derivative like of oripavine.
 
atara said:
I don't really like these "chemical weapon" threads, personally.
Click to expand...

N-phenethyletorphine? Could be. It isn't so much a "weapon" as per knowing if it were possible and active. If it were weaker it would be more interesting than if it were stronger (kind of how Oxycodone's two changes by themselves each make the molecule weaker, but together they make it much stronger). So strength is not an interest even with aspects of abuse of the substance (personally higher doses of negligibly-toxic-at-such-doses drugs of light strength seem to be more euphoric, if that is they don't have a cut off cap. to how many mg work like with Codeine). I'd be very interested to know the 14 change that makes the morphinan more mu-affable and the oripavine related active bridge variants together render the molecule still an agonist but lightly so, or completely inactive. These results would be more educational and wanted for me. So if intentions in threads count or not (and usually I think a lot seem to believe they do; esp. those with an invested interest in the perception of the site's integrity; admins etc)
 
You have your O-chem a bit mixed up (mine is as well), but yes, the substitution likely increases potency if you plug it into a SAR/QSAR program.......

Oh, and structurally similar and potent drugs like the veterinarian drug "Immobilon" (aka etorphine) are actually used safely in clinical practice, such as dihydroetorphine, which is not readily available in the states or EU, but is prescribed for opioid addiction treatment in Asia (particularly, China). Hands down, it beats buprenorphine, but I still think methadone is the best maintenance drugs readily accessible.
 
Nagelfar said:
Apparently 'isopentyl' at the "R" character on the above 2D image of a bridged oripavine derivative of the morphinan mu-agonist is 9,000+ x the potency of morphine. Taking the 14- substitution in PPOM (14-Phenylpropoxymetopon), alone, makes the latter "thousands" of time more potent than morphine. Would it multiply the isopentyl oripavine derivative the same (and could such be acetylated too like acetorphine is to etorphine as a oripavine in addition to it being the isopentyl at that 'R' site without losing the optimized affinity?) Also would these theoretically affect the binding of either or as an agonist? Could more be added like an azide group at the 6 position (like in azidomorphine) or a hydrazone as in the morphazones? What else could be done to make a morphinan have potency to put the fentanyl analogues to shame? (Which is basically my goal here)

Could someone draw an optimized 2D molecule that could be workable (exist without SAR impasse via entering through the realm of impossible physics which I am ignorant of) according to those main tenets I have posited above?
Click to expand...

Yes, apparently isoamyl (3-methylbutyl) gives a drug even more potent than etorphine (my source says 9200x morphine). Anyway, I understand your post, as the others, that you still want to add something at C14. And that's impossible as annelation gives another ring and 4 different groups are already connected to C14.

But all those high-potency oripavine derivatives with agonist properties are actually useless compared to good old morphine. They do have a rush, they do act like opioid agonists but they lack that "magic" of relatively weak opioids like morphine or hydromorphone. I see no point in syntheses of those ultrapotent monsters.

There is a lot of potent opioid analgesics that are simply 14-substituted and they don't have that additional ring. 14-pentylaminomorphin-6-one is a few hundreds as potent as fentanyl and it's quite similar in hydromorphone in action. It's got a very fast onset and short duration.

BTW, for N-substitution 2-(furan-2-yl)ethyl and 2-(thiophen-2-yl)ethyl are better choices than phenylethyl. They give more active compounds.
 
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Are you sure that, in this case, altering the N-substituant works as well? I've never seen any research on the subject. Larger substuants work on 14-(m)ethoxy metopon & that looks pretty potent. Interesting that the 5-methyl is very important - it lend's the material purer agonist activity.
 
In fact, there are some general rules:

morphine QSAR

1. Enantiomeric dextrorotatory morphine is devoid of analgesic activity.

2. A trans-ring junction between rings Band C drastically reduces analgesic potency.

3. A phenolic hydroxyl at C-3 is important for analgesia, but not necessary. The 3,6-deoxy-derivative is equipotent to morphine but may represent metabolic hydroxylation.

4. Other substituents on the A-ring decrease or eliminate activity.

5. Substituents at C-l0 in the B-ring maintain or decrease morphinomimetic
activity.

6. Some of the chemical features of the Coring of morphine are relatively noncrucial: removal of the double bond (7,9) or the alcohol at C-6. Numerous other chemical modifications are also compatible with enhanced analgesic activity: a C-5 methyl group, oxygenation or alkylation at C-6, phenylalkyl substitution at 7-beta, and short alkyl substitution at 8-beta.

7. Hydroxyl substitution at the BC-ring junction (C-14), as well as its acyl derivatives, strongly enhances analgesia. Other substituents eliminate activity.

8. The methyl group on the amine is not optimal. Replacement by arylalkyl or functionalized arylalkyl groups increases morphinomimetic activity severalfold. Replacement by N-lower alkyl (propyl, allyl, cyclopropylmethylene) produces morphine antagonists.

9. Addition of a sixth ring by Diels-Alder additions to thebaine can increase either morphine agonist or antagonist activity by at least four orders of magnitude.

Diels-Alder adducts

1. The substitution on the carbinol group at C-7 is important: C-19 tertiary alcohols have a higher analgesic potency than secondary ones; however, in cases where both C7-alpha and C-7beta 3 epimers have been evaluated, only slight differences in potency have been observed in the pairs.

2. Highest activities have been found when a moderate disparity in size between the two groups on the C-19 alcohol, R" and R', exists. One substituent should be small, that is, H or CH3. Maximal analgesic activity is then found when the second substituent is a 3- to 5- hydrocarbon chain; further lengthening results in a steady decrease in activity.

3. The diastereomers of unsymmetrical tertiary alcohols can show markedly different analgesic properties, the 19R configuration being the more potent morphine agonist.

4. The comparable 6, 14-endoetheno and 6,14-endoethano analogs show only marginal differences in analgesic agonist or antagonist potency.

5. The oripavine derivatives (C-3 hydroxyl) or their C-3 acetylated analogs are more potent analgesics than the thebaine bases (C-3 methoxy).

6. The piperidino nitrogen should be tertiary, the secondary amines being less active as agonists. Increasing the size of the nitrogen substituent beyond methyl steadily decreases analgesic activity. Some N-allyl and N-cyclopropylmethyl thebaine and oripavine derivatives
of tertiary alcohols are potent antagonists.

7. The piperidine and ether rings should remain intact. Substitution on the piperidine ring near the basic nitrogen creates potent antitussives.



This information is almost 30 years old so if anyone has more modern data, please share. I seem to remember that the benzopyrene analogs were pretty strong when substituted for the A,B & C rings in the morphine molecule (x60 if I remember correctly). They also miss quite a lot of possible C-14 substituants (semaphorine for example).
 
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