4DQSAR
Bluelighter
- Joined
- Feb 3, 2025
- Messages
- 5,523
US patent 3905987 covers a number of homologues of doxicopamine. ChemOffice reveals that the aromatic ring, amine and oxygen-containing function all overlay those of US3928626A which covers ciramadol. Both are chiral but only the latter was considered as a medicine containing one enantiomer. But the patent shows that in both cases, it's the same enantiomer that is responsible for the activity.
I think it's important to note that if the aromatic is a meta pyridine, that's a bioisostere of a meta phenol as evidenced by analogues of fentanyl and phenapromide containing a meta pyridine in place of a benzene being mixed agonists.
With all such research, we are limited by what pharmacutical companies choose to make public. The 3-phenyl-3-3-amino propanamide class of ligand also overlays AND overlays fentanyl. The question raised is that while most people have at least heard of BDPC, most didn't seem to note that replacing that para bromo benzene with a meta phenol resulted in a robust antagonist.
Sadly Dan's no longer around to ask but from what I know, the simpler compounds including what someone has decided to name dimetadine were essentially the result of teasing apart the various activites of PCP analogues which were known to act on the opiate receptors. I believe he built Dreiding models of each one and was able to use the data gathered from studying the simpler compounds and work out that although seemingly unrelated to fentanyl, BDPC overlays it perfectly. Obviously almost none of this was ever made public but it wasn't actually none of the above were the first benylamine opioids. That accolade goes to:
Analgetic activity of some δ-amino ketones and their derivatives
https://sci-hub.st/10.1021/jm00320a007
And is revisited by:
Design, Synthesis and Biological Evaluation of 3-amino-3-Phenyl Propanamide Derivatives
Of the latter, the only thing I can add with a certain degree of certainty is that once again, that chiral amine once again follows those doxicopamine analogues and ciramadol. Sadly, due to changes in UK law it was not possible to futher investigate but it's worth noting that if you feed in fentanyl and example 4a, the two overlay in their minimum-energy conformation.
Of course it was tempting to see if adding a benzylic hydroxyl to the B-ring, but I believe Dan tried adding methyl side-chains to BDPC where the lipophilic pocket of 3MF would be but as far as I know either it was never tested or did not work.
More generally I'm just more interested in the benzylamine opioids. Other examples exist (lefetamine and the derivatives developed Dainippon Pharmaceutical Co. in the 70s for example) and it's interesting to note that Dan considered cebranopadol to be the 'spiritual successor' to his work - when I sent him the papers he was really happy and spend a full week reviewing it all. In that case side-chains (including allyl as seen in allylprodine) were also tested and abandoned. So I think it reasonable to suggest it's 'case closed' in terms of alkyl side-chains akin to 3MF.
Although the 'morphine rule' was abandoned after the inventors had to first add 'the fentanyl modification' and when more arrived realized that the exceptions outweighted the rule, it does appear that researchers probably just look at what's out there and benzylamine opioids being quite rare makes them an unattractive class of lead compound but as you can see, they have been known of for over sixty years so it isn't really novel, more overlooked.
I think it's important to note that if the aromatic is a meta pyridine, that's a bioisostere of a meta phenol as evidenced by analogues of fentanyl and phenapromide containing a meta pyridine in place of a benzene being mixed agonists.
With all such research, we are limited by what pharmacutical companies choose to make public. The 3-phenyl-3-3-amino propanamide class of ligand also overlays AND overlays fentanyl. The question raised is that while most people have at least heard of BDPC, most didn't seem to note that replacing that para bromo benzene with a meta phenol resulted in a robust antagonist.
Sadly Dan's no longer around to ask but from what I know, the simpler compounds including what someone has decided to name dimetadine were essentially the result of teasing apart the various activites of PCP analogues which were known to act on the opiate receptors. I believe he built Dreiding models of each one and was able to use the data gathered from studying the simpler compounds and work out that although seemingly unrelated to fentanyl, BDPC overlays it perfectly. Obviously almost none of this was ever made public but it wasn't actually none of the above were the first benylamine opioids. That accolade goes to:
Analgetic activity of some δ-amino ketones and their derivatives
https://sci-hub.st/10.1021/jm00320a007
And is revisited by:
Design, Synthesis and Biological Evaluation of 3-amino-3-Phenyl Propanamide Derivatives
Of the latter, the only thing I can add with a certain degree of certainty is that once again, that chiral amine once again follows those doxicopamine analogues and ciramadol. Sadly, due to changes in UK law it was not possible to futher investigate but it's worth noting that if you feed in fentanyl and example 4a, the two overlay in their minimum-energy conformation.
Of course it was tempting to see if adding a benzylic hydroxyl to the B-ring, but I believe Dan tried adding methyl side-chains to BDPC where the lipophilic pocket of 3MF would be but as far as I know either it was never tested or did not work.
More generally I'm just more interested in the benzylamine opioids. Other examples exist (lefetamine and the derivatives developed Dainippon Pharmaceutical Co. in the 70s for example) and it's interesting to note that Dan considered cebranopadol to be the 'spiritual successor' to his work - when I sent him the papers he was really happy and spend a full week reviewing it all. In that case side-chains (including allyl as seen in allylprodine) were also tested and abandoned. So I think it reasonable to suggest it's 'case closed' in terms of alkyl side-chains akin to 3MF.
Although the 'morphine rule' was abandoned after the inventors had to first add 'the fentanyl modification' and when more arrived realized that the exceptions outweighted the rule, it does appear that researchers probably just look at what's out there and benzylamine opioids being quite rare makes them an unattractive class of lead compound but as you can see, they have been known of for over sixty years so it isn't really novel, more overlooked.
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