MOR Superagonists

[AlsoTapered]

Library Genesis

libgen.pm

There are several endogenous MOR ligands but it's interesting to note that BU72 is, seemingly, the only example of a superagonist. Now it's clear why this isn't an activity sought in any medicine but it does at least suggest that totally synthetic opioids MIGHT actually be superagonists since the efficacy of most has not been explored. The MOR affinity of BU72 was measured as 0.06 nM (NOT μM) and their ARE synthetics in this range.

Library Genesis

libgen.pm

Notice that the A,B and C rings of BU72 are identical to morphine and the D ring only differs only in the stereochemistry of the 6-substituant.

 

[Foreigner]

One thing I've always found amazing during my studies of biochemistry is how stereochemistry can be basically identical except there can be just one additional atom, or one minor configurational difference, and the molecule will have significantly stronger or different impacts. It's mind blowing.

 

[someguyontheinternet]

A small change in position of a change in atom can have a big impact on how things line up for hydrogen bonding or make h bonding much less electronically ideal. Or changes in electronic properties of a swapped atom changes the properties of how the structure is able to bond or ionize. Protein binding sites are usually highly specific in their organization

 

[AlsoTapered]

Hence the joke in medicinal chemistry referred to as 'the magic methyl' i.e. any tiny alteration in a ligand that has a massive effect on activity. Usually the joke is that said 'magic methyl' is in a position which means the lab-workers have to develop an entirely new synthetic pathway.

 

[AlsoTapered]

BTW not to be confused with methyl fluorosulfonate (a very powerful methylating agent). It's now banned from most labs because it killed several chemists who failed to read the MSDS and use appropriate safety procedures.

 

[AlsoTapered]

Structural insights into μ-opioid receptor activation

Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To understand the structural basis for μOR activation, we obtained a 2.1 Å X-ray crystal structure of the μOR ...

www.ncbi.nlm.nih.gov