SUBJECT OVERVIEW:
We learn from Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 18.1 N-Substituted 14-Phenylpropyloxymorphinan-6-ones with Unanticipated Agonist Properties:
Extending the Scope of Common Structure-Activity Relationships
J. Med. Chem. 2003, 46, 1758-1763
It is believed by someone much more well versed in opioid pharmacology that the ideal opioid would be a ?/?-agonist and ORL1(?3)-antagonist.
I wonder, between the two above cited 17-substituted 14-phenylpropoxynoroxymorphone structures, which one would be better to go with while keeping in mind the above provided pharacological considerations: choosing the N-propyl so that there was greater mu selectivity but at the cost of sigma affinity being less than K affinity OR N-CPM so that sigma affinity is increased to greater than half of mu but with K affinity increased to almost as much as mu? This question is only food for thought because I will be presenting below other modifications which I believe will likely be more promising. Also, in case anyone is not familiar with opioid receptor subtypes:
Pure µ agonists (like fentanyl) lack any appreciable euphoria and in the author's opinion not worth bothering with.
Any appreciable kappa opioid agonism is known to produce dysphoric effects such as disassociation and hallucination. Even people who enjoy K agonists such as salvinorin A would not likely want that experience mixed in with the basking in warmth and comfort that can be found in opioid bliss. So in this comparison, based on the negative effects associated with opioids showing a lack of significant preferance of µ over K, I'd say it would be most important to avoid those K effects, and so in this case the N-propyl structure would likely be the better candidate (and an exceedingly potent one too!)...
There is another relevant article that I would greatly appreciate if someone could kindly share:
Synthesis of N-isobutylnoroxymorphone from naltrexone by a selective cyclopropane ring opening reaction.
Med Chem Lett. 2008 Sep 15;18(18):4978-81.
doi: 10.1016/j.bmcl.2008.08.019. Epub 2008 Aug 12.
From the abstract we find that they selectively open the cyclopropyl ring of naltrexone (using Pt(IV) oxide, hydrobromic acid and H2), affording N-isobutynoroxymorphone. They claim that, surprisingly, it produced dose dependent analgesic effects in the mouse acetic acid writhing test, yielding an ED(50) of 5.05 mg/kg, sc. (roughly equivalent to morphine).
BUT, I surmise that this article (or at least the abstract) is mentioning only part of the action. I propose that N-isobutyl-noroxymorphone is most likely a mixed agonist/antagonist (AKA dualist). The reasoning for this is because N-propyl-noroxymorphone, which might be considered the closest N-substituted analogue, has been reported to be both one of a number of N-sub'd dualists as well as specifically reported to be a pure antagonist (See: Current Medicinal Chemistry. 1996;1(6):427-29 and Binding properties of the pure opioid antagonist [3H](N-propyl)-noroxymorphone in rat brain membranes., Neurobiology (Bp). 1993;1(4):327-35.).
So I think that N-isobutyl-noroxymorphone is most likely a dualist but has only been examined once, to my knowledge, and was likely only examined with regard to it's agonist properties.
Further related work is found in:
14ß-O-Cinnamoylnaltrexone and Related Dihydrocodeinones are Mu Opioid Receptor Partial Agonists with Predominant Antagonist Activity
J. Med. Chem. 2009, 52, 1553–1557
The most noteworthy compound discussed is 14-O-Cinnamoylnaltrexone which has a reported Ki for the mu receptor of 0.40 and selectivity ratios: K/µ=8.5 and sigma/µ=9.0. "It is of interest to compare the activity of 14-cinnamoylnaltrexone with that of the phenylpropyl ether which is structurally similar in having a three-carbon chain linking the side chain aromatic ring to the C14 oxygen atom. The ether (2a) in vivo gave a full response in a battery of thermal antinociceptive assays with potency up to 400 times greater than that of morphine. In comparison, the cinnamoyl ester has much more modest in vitro and in vivo MOR agonist activity. It must be assumed that the relative conformational restraint of the alpha-beta unsaturated ester prevents an optimum interaction with MOR in the preferred agonist conformation". The optimum conformation to which they speak of, by the way, is with the aromatic ring (14-phenylpropoxy, 14-hydrocinnamoyl, etc) perpedicular and slightly below morphinan ring C.
The conformational restraint hypothesis proposed above appears reasonable considering that the combined effect of the carbonyl and alkene portions of the cinamoyl group essentially lock up all three chain carbons and allowing very limited movement besides the angled rotational freedom at the oxygen which connects the ester and the rotation of the phenyl ring. BUT if this were the complete explanation then how could one explain the significant potency of 14-cinnamoyloxycodeinone, which is reported to be a potent agonist of roughly 178x morphine determined via the tail clip method in mice ("QSAR of Narcotic Analgetic Agents" NIDA Research Monograph 1978 (22): 186–196. PMID 30907.). What is even more strange is that 14-hydrocinnamoyloxycodeinone, which should have greater conformational freedom due to the reduction of the alkene bond, is actually found by the same method to be slightly weaker with a tested potency of 115x morphine. The one part of the established SAR that does actually make sense is that the relatively weaker activity compared to the 14-phenylpropoxy ethers can be expected because of the 3-methyl ether of the codeinones compared to the morphones. But the question that still remains is does the 7-8 double bond of the codeinones somehow assist both of these 14-esters, especially the most restricted ester (cinnamoyl) into attaining the optimal conformation? Based on the results of 14-cinnamoylnaltrexone one would expect 14-cinnamoylcodeinone to have even less agonist activity than 14-hydrocinnamoylcodeinone, but the opposite is the case. If all reports are true and complete then the only explanation I can imagine is that the 7-8 double bond must somehow be helping orient the esters, especially the unsaturated ester, into the optimal conformation. I have yet to find a plausible explanation via Chemdraw 3-D.
SYNTHETIC APPROACHES USING NALTREXONE AND POTENTIAL PRODUCTS:
In the first paper that was listed above (agonist naltrexone analogues), the synthesis of 14-phenylpropoxy-naltrexone starts with 14-hydroxycodeinone being deprotonated by NaH and then alkylated with cinnamyl bromide. Then both the cinnamyl double bond and the 7-8 double bond is reduced via Pd/C and hydrogen.
This alkylation of alcohols to form ethers is not particularly friendly to the hobby chemist as it requires a very hazardous base (NaH) and an intert atmosphere (unless someone can suggest a more accessible alternative?). What is interesting though is that they do not alkylate with hydrocinnamyl bromide but rather reduce the double bond after alkylation.
I propose that N-isobutyl-14-hydrocinnamoyl-nornaltrexone and/or N-isobutyl-14-hydrocinnamoyl-7,8-dihydronormorphine may be strong opioids which can be attained through relatively easy steps. First, reaction of naltrexone with 2.2 equivalents of cinnamoyl bromide in pyridine (water-sensitive) would yield 3,14-dicinnamoylnaltrexone. Then Catalytic Transfer Hydrogenation with Pd/C 10%, formic acid and a bit of potassium hydroxide at r.t. will definitely open up the n-cyclopropylmethyl to form n-isobutyl, reduce the 14-cinnamoyl to 14-hydrocinnamoyl, most likely reduce off the 3-ester and probably will convert the 6-keto to an alcohol.
Whether or not the 6-keto group is reduced, either structure should prove to be more selective and give better effects with the n-isobutyl group (more similar to the n-propyl) than similar structures with the n-cyclopropylmethyl group. Cyclopropyl rings are very reactive to ring-opening reductions (more reactive than alkenes to reduction) BTW.
Naltrexone is readily available. Who has the time and the resources to check out whichever potent opioid is the actual product from these two relatively easy reactions? Both structures are able to obtain the ideal conformation for opioid mu receptor agonism.
We learn from Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 18.1 N-Substituted 14-Phenylpropyloxymorphinan-6-ones with Unanticipated Agonist Properties:
Extending the Scope of Common Structure-Activity Relationships
J. Med. Chem. 2003, 46, 1758-1763
- Most excitingly, 14-phenylpropoxy-naltrexone is found surprisingly to be a potent agonist (Ki for mu receptor: 0.34, 600x morphine in TF) BUT has poor selectivity for the µ receptor with ratios of K/µ=1.96 and ?/µ=1.84 (so slightly less than double the preference for µ (larger numbers mean higher selectivity for µ receptor).
- 14-phenylpropoxy-N-propyloxymorphone (swapping the N-CPM in the above structure for N-propyl) is even found to be even more potent (950x morphine in TF) and has better µ selectivity of K/µ=4.11 and ?/µ=10.3.
- morphine Ki selectivity ratios: K/µ and ?/µ are 17.3 and 33.1 respectively.
- Oxymorphone (known to be quite euphoric) ratios are 63 and 83.
- 14-methyloxymorphone, ratios are 102 and 48. (Sounds like this might be better euphoria than oxymorphone )
- 14-methoxymetopon, which is a very powerful µ agonist, ratios are 13217 and 1178.
It is believed by someone much more well versed in opioid pharmacology that the ideal opioid would be a ?/?-agonist and ORL1(?3)-antagonist.
I wonder, between the two above cited 17-substituted 14-phenylpropoxynoroxymorphone structures, which one would be better to go with while keeping in mind the above provided pharacological considerations: choosing the N-propyl so that there was greater mu selectivity but at the cost of sigma affinity being less than K affinity OR N-CPM so that sigma affinity is increased to greater than half of mu but with K affinity increased to almost as much as mu? This question is only food for thought because I will be presenting below other modifications which I believe will likely be more promising. Also, in case anyone is not familiar with opioid receptor subtypes:
Pure µ agonists (like fentanyl) lack any appreciable euphoria and in the author's opinion not worth bothering with.
Any appreciable kappa opioid agonism is known to produce dysphoric effects such as disassociation and hallucination. Even people who enjoy K agonists such as salvinorin A would not likely want that experience mixed in with the basking in warmth and comfort that can be found in opioid bliss. So in this comparison, based on the negative effects associated with opioids showing a lack of significant preferance of µ over K, I'd say it would be most important to avoid those K effects, and so in this case the N-propyl structure would likely be the better candidate (and an exceedingly potent one too!)...
There is another relevant article that I would greatly appreciate if someone could kindly share:
Synthesis of N-isobutylnoroxymorphone from naltrexone by a selective cyclopropane ring opening reaction.
Med Chem Lett. 2008 Sep 15;18(18):4978-81.
doi: 10.1016/j.bmcl.2008.08.019. Epub 2008 Aug 12.
From the abstract we find that they selectively open the cyclopropyl ring of naltrexone (using Pt(IV) oxide, hydrobromic acid and H2), affording N-isobutynoroxymorphone. They claim that, surprisingly, it produced dose dependent analgesic effects in the mouse acetic acid writhing test, yielding an ED(50) of 5.05 mg/kg, sc. (roughly equivalent to morphine).
BUT, I surmise that this article (or at least the abstract) is mentioning only part of the action. I propose that N-isobutyl-noroxymorphone is most likely a mixed agonist/antagonist (AKA dualist). The reasoning for this is because N-propyl-noroxymorphone, which might be considered the closest N-substituted analogue, has been reported to be both one of a number of N-sub'd dualists as well as specifically reported to be a pure antagonist (See: Current Medicinal Chemistry. 1996;1(6):427-29 and Binding properties of the pure opioid antagonist [3H](N-propyl)-noroxymorphone in rat brain membranes., Neurobiology (Bp). 1993;1(4):327-35.).
So I think that N-isobutyl-noroxymorphone is most likely a dualist but has only been examined once, to my knowledge, and was likely only examined with regard to it's agonist properties.
Further related work is found in:
14ß-O-Cinnamoylnaltrexone and Related Dihydrocodeinones are Mu Opioid Receptor Partial Agonists with Predominant Antagonist Activity
J. Med. Chem. 2009, 52, 1553–1557
The most noteworthy compound discussed is 14-O-Cinnamoylnaltrexone which has a reported Ki for the mu receptor of 0.40 and selectivity ratios: K/µ=8.5 and sigma/µ=9.0. "It is of interest to compare the activity of 14-cinnamoylnaltrexone with that of the phenylpropyl ether which is structurally similar in having a three-carbon chain linking the side chain aromatic ring to the C14 oxygen atom. The ether (2a) in vivo gave a full response in a battery of thermal antinociceptive assays with potency up to 400 times greater than that of morphine. In comparison, the cinnamoyl ester has much more modest in vitro and in vivo MOR agonist activity. It must be assumed that the relative conformational restraint of the alpha-beta unsaturated ester prevents an optimum interaction with MOR in the preferred agonist conformation". The optimum conformation to which they speak of, by the way, is with the aromatic ring (14-phenylpropoxy, 14-hydrocinnamoyl, etc) perpedicular and slightly below morphinan ring C.
The conformational restraint hypothesis proposed above appears reasonable considering that the combined effect of the carbonyl and alkene portions of the cinamoyl group essentially lock up all three chain carbons and allowing very limited movement besides the angled rotational freedom at the oxygen which connects the ester and the rotation of the phenyl ring. BUT if this were the complete explanation then how could one explain the significant potency of 14-cinnamoyloxycodeinone, which is reported to be a potent agonist of roughly 178x morphine determined via the tail clip method in mice ("QSAR of Narcotic Analgetic Agents" NIDA Research Monograph 1978 (22): 186–196. PMID 30907.). What is even more strange is that 14-hydrocinnamoyloxycodeinone, which should have greater conformational freedom due to the reduction of the alkene bond, is actually found by the same method to be slightly weaker with a tested potency of 115x morphine. The one part of the established SAR that does actually make sense is that the relatively weaker activity compared to the 14-phenylpropoxy ethers can be expected because of the 3-methyl ether of the codeinones compared to the morphones. But the question that still remains is does the 7-8 double bond of the codeinones somehow assist both of these 14-esters, especially the most restricted ester (cinnamoyl) into attaining the optimal conformation? Based on the results of 14-cinnamoylnaltrexone one would expect 14-cinnamoylcodeinone to have even less agonist activity than 14-hydrocinnamoylcodeinone, but the opposite is the case. If all reports are true and complete then the only explanation I can imagine is that the 7-8 double bond must somehow be helping orient the esters, especially the unsaturated ester, into the optimal conformation. I have yet to find a plausible explanation via Chemdraw 3-D.
SYNTHETIC APPROACHES USING NALTREXONE AND POTENTIAL PRODUCTS:
In the first paper that was listed above (agonist naltrexone analogues), the synthesis of 14-phenylpropoxy-naltrexone starts with 14-hydroxycodeinone being deprotonated by NaH and then alkylated with cinnamyl bromide. Then both the cinnamyl double bond and the 7-8 double bond is reduced via Pd/C and hydrogen.
This alkylation of alcohols to form ethers is not particularly friendly to the hobby chemist as it requires a very hazardous base (NaH) and an intert atmosphere (unless someone can suggest a more accessible alternative?). What is interesting though is that they do not alkylate with hydrocinnamyl bromide but rather reduce the double bond after alkylation.
I propose that N-isobutyl-14-hydrocinnamoyl-nornaltrexone and/or N-isobutyl-14-hydrocinnamoyl-7,8-dihydronormorphine may be strong opioids which can be attained through relatively easy steps. First, reaction of naltrexone with 2.2 equivalents of cinnamoyl bromide in pyridine (water-sensitive) would yield 3,14-dicinnamoylnaltrexone. Then Catalytic Transfer Hydrogenation with Pd/C 10%, formic acid and a bit of potassium hydroxide at r.t. will definitely open up the n-cyclopropylmethyl to form n-isobutyl, reduce the 14-cinnamoyl to 14-hydrocinnamoyl, most likely reduce off the 3-ester and probably will convert the 6-keto to an alcohol.
Whether or not the 6-keto group is reduced, either structure should prove to be more selective and give better effects with the n-isobutyl group (more similar to the n-propyl) than similar structures with the n-cyclopropylmethyl group. Cyclopropyl rings are very reactive to ring-opening reductions (more reactive than alkenes to reduction) BTW.
Naltrexone is readily available. Who has the time and the resources to check out whichever potent opioid is the actual product from these two relatively easy reactions? Both structures are able to obtain the ideal conformation for opioid mu receptor agonism.