Neuroscience Address-Message Theory and Requirements of an Opiate Antagonist

[AlsoTapered]

While I don't hold out much faith of an answer - has anyone found a single example of an opiate antagonist that doesn't bear meta -OH group on the A-aromatic?

I investigated the 1S-(S,S) enantiomer of viminol which was initially stated to possess antagonist activity but in the paper:

Title: Synthesis and pharmacological investigation of the 3-analogs of viminol
Series: European Journal of Medicinal Chemistry 1988-nov vol. 23 iss. 6
Author(s): Marco de Amici; Carlo de Micheli; Fabio Platini; Davide Della Bella; Ida Caramazza

The binding inhibition of 1S-(S,S)-viminol (tested using displacement of 3H Dihydromorphine was) >300 nM compared to 2 nM for the 1S-(R,R).

in both a patent and a paper animal models appeared to demonstrate antagonist properties but I would argue that if a compound doesn't notably compete for the opiate receptors (DHM being a non-selective agonist), the subjective studies in fact suggest that the responses elicited by the 1S-(S,S) enthiomer are not mediated by the opiate receptors.

I can find NO other examples of opiate antagonists that do not bear that meta -OH (or bioisostere).

 

[polymath]

There exist peptides that block mu receptors, and no natural amino acid has a meta-hydroxyl. So I guess there should be non-peptide antagonists too.

 

[AlsoTapered]

There exist peptides that block mu receptors, and no natural amino acid has a meta-hydroxyl. So I guess there should be non-peptide antagonists too.

Tyrosine can have a L-m-OH and all the opiate antagonist peptides I've looked at require said moiety. Natural and per corpus obviously have slightly different meanings but the body DOES modify amino-acids.

 

[polymath]

If the relevant part is just where the hydroxyl resides in the 3d structure, relative to the other necessary functional groups, then that explains why the p-OH of tyrosine is sufficient for this. Maybe there also exists an opioid where it's a thiophenol instead of -OH.

 

[AlsoTapered]

If the relevant part is just where the hydroxyl resides in the 3d structure, relative to the other necessary functional groups, then that explains why the p-OH of tyrosine is sufficient for this. Maybe there also exists an opioid where it's a thiophenol instead of -OH.

Since a carboxamide (-C(O)NH2) moiety has been proven to be a bioisostere in an opioid agonists & antagonist, 'or bioisostere thereof' has been demonstrated, but the chemical properties of a thiophenol mean at physiological pH, it won't work - BUT willing to be proven wrong.

Replacing a m-phenol with an o-pyidiyl moiety seems to produce mixed agonist/antagonist activity because the adjacent C is more H donating so has been seen in mixed agonists like propiram, but I cannot find it in a pure(ish) antagonist. A few more modern opioids have this o-pyridyl moiety and are supposed to be G-coupled protein triggered and not b-arrestin recruiting BUT their is still a question as to the perceived activity simply being of low efficacy so should more accurately be considered partial agonists.

BTW the carboxamide is chiral due to orientation relative to aromatic BUT the body cannot metabolise them so duration was greatly increased. A lot of people were surprised by this unexpected chirality... which merely shows the value of viewing molecules in (pseudo) 3D over 2D.

 

[polymath]

Looking at this paper, an amine group is also a bioisostere, but not as good as carboxamide.

3-Carboxamido analogues of morphine and naltrexone. synthesis and opioid receptor binding properties - PubMed

In response to the unexpectedly high affinity for opioid receptors observed in a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group, we have prepared the corresponding 3-CONH(2) analogues of morphine and naltrexone. High affinity (K(i)=34 and...

pubmed.ncbi.nlm.nih.gov

This was quite interesting, I'm not sure if I've seen that before (probably I have but can't remember).

 

[AlsoTapered]

Library Genesis

libgen.pm

That's the index paper for use of carboxamido groups - but it just demonstrates that H donation is the key facet of action.

Like the o-pyridiyl, it's making a hydrogen-bond possible at the meta position.