I note a new class of opioid. It contains 4 of the 5 key moieties of a strong opioid, an ideal biosteric minimum and a clear metabolic pathway. If you go back to the 60s, Janssen produced some closely related compounds. In that case, a figure of x450 pethidine (x45 M) was given but that p-Br is important in obtaining the correct biosteric minimum so it may be more potent.
What I DID notice was that it is closely related to bezitramide (Bugodin™). While the n-propenoyl of bezitramide is suppose to be hydrolyzed by the GI tract, bezitramide is often given via bolus and so bezitramide rather than N-despropenoyl bezitramide will be the active drug.
Just to be clear, the x450 pethidine figure was based on writhing tests. The study was such a long time ago that the Straub tail-test wasn't used so it's hard to guess it's potency in man. It's of academic interest because it shows that rigid bioisosteres of the amide moiety produce activity and MAY go some way in understanding the active conformation of fentanyl.
Bezitramide it also interesting as an example in which a nitrile replaces the more common ketone moiety. Primary amides are also seen in related compounds and so their is a question over what these moieties DO. It may well be that they are simply space-filling. The methyl side-chain of methadone famously rotates one of the benzene rings and is a requirement, but it's not clear unless one overlays methadone & normethadone in a minimum-energy conformation. Dextromoramide shows a refinement of the specific rotation.
What I DID notice was that it is closely related to bezitramide (Bugodin™). While the n-propenoyl of bezitramide is suppose to be hydrolyzed by the GI tract, bezitramide is often given via bolus and so bezitramide rather than N-despropenoyl bezitramide will be the active drug.
Just to be clear, the x450 pethidine figure was based on writhing tests. The study was such a long time ago that the Straub tail-test wasn't used so it's hard to guess it's potency in man. It's of academic interest because it shows that rigid bioisosteres of the amide moiety produce activity and MAY go some way in understanding the active conformation of fentanyl.
Bezitramide it also interesting as an example in which a nitrile replaces the more common ketone moiety. Primary amides are also seen in related compounds and so their is a question over what these moieties DO. It may well be that they are simply space-filling. The methyl side-chain of methadone famously rotates one of the benzene rings and is a requirement, but it's not clear unless one overlays methadone & normethadone in a minimum-energy conformation. Dextromoramide shows a refinement of the specific rotation.
