What structural changes give antagonist/reduced intrinsic activity in opioid receptor

[aced126]

Does anyone know of any studies evaluating the pharmacophore requirements of antagonist activity at MOR? What made me think about this was the following:

Naltrexone: full antagonist

Nalbuphine: partial agonist (intrinsic activity = 47% )

My questions:

1) Does substitution at carbon 6 affect intrinsic activity?

2) Is it such that a cyclobutylmethyl subsitution increases intrinsic activity from 0 (antagonist) to almost 50% (agonist).

I'll edit more in time.

 

[farmacista]

usually oxidation at carbon 6 increases potency if the 7/8 double bound is saturated and/or there is an OH at the 14 position, while reduces potency in morphinone without moving action from agonist to antagonist (for istance naloxone and nalorphine are both full antagonist at the mu receptor) so i think that is the substitution on the nitrogen that changes intrinsic activity

 

[belligerent drunk]

I would go with the thought that cyclopropane moiety can behave as a pi double bond (at least in chemical reactions), which makes it very similar to naloxone (which is also an antagonist/very weak partial agonist), while cyclobutane doesn't. Other than that, the only other difference would be the absence of hydrogen bond donor at the 6th position in the case of ketone, I guess, but you already know that doesn't necessarily remove agonist activity.

 

[dopamimetic]

Isn't naltrexone an inverse agonist (like naloxone) and not just a full antagonist?

 

[serotonin2A]

Isn't naltrexone an inverse agonist (like naloxone) and not just a full antagonist?

Yes...naloxone and naltrexone are inverse agonists. Few antagonists are completely neutral.

 

[belligerent drunk]

I'm sorry, I meant to say weak inverse agonist. Sorry for the confusion.

 

[aced126]

How can a cyclopropyl group behave as a pi bond?

 

[belligerent drunk]

https://en.wikipedia.org/wiki/Cyclopropane#Structure_and_bonding

Here's some kind of explanation.