Question about reduced efficacy of partial agonists.

Factual Questions
1

I’m not up on molecular biology - just a little interested in how drugs work- and I’m curious how a partial agonist reduces efficiacy. I’m sure there’s thousands of different ways depending on what pathways and proteins etc, but even one example will help.

Here’s what I think I know: a partial agonist, having a different molecular structure than the full agonist, deconforms the receptor protein in a different way making the intracellular component react differently. What I’m curious about is how the change allows for partial efficacy. Does the protein that binds on the intracellular side not bind as strongly or something making it more easily decoupled? Is there a simple illustrative example you can think of and impress in layman’s terrms? Thanks in advance!

2

I think you have it.

Here is an abstract from a relevant article. I bolded the part you are interested in. But basically, when an agent binds to a receptor, it may activate it fully (agonist), it may block the receptor site without activation (antagonist), or behave in-betweenly. This in-between activity is not much discussed in my experience (except to say it happens and maybe quantify the effect), but I also am not a biochemist or molecular biologist.

I was a chemist (ages ago) and I feel your explanation is correct. When an agonist binds to a receptor, it deforms the protein to cause some effect (eg- signaling by enzymatic action or opening a pore, etc.). A partial agonist can cause the same event to happen, but not as well, presumably because the protein is not optimally deformed. Meanwhile, it’s sitting on a receptor site that could be used by the real agonist, so it is also a partial antagonist (at least to a stimulated system).

This is used with opioids. A partial agonist gives enough stimulation to decrease cravings and prevent withdrawal, while at the same time it blocks the receptors from fully reacting to a dose of street drugs.
ABSTRACT
J Cardiovasc Pharmacol. 1983;5 Suppl 1:S8-15.
Intrinsic activity: partial agonists and partial antagonists.

Ariëns EJ.
Abstract
The effect of bioactive agents in many, if not most, cases should be considered as the result of an interaction among molecules of the active agent, the drug, and particular molecular sites of action, receptors (sometimes enzymes), in the biological object. In those cases in which a drug-receptor interaction is involved, two essential parameters should be distinguished, namely, the affinity of the active agent to its receptor, and the intrinsic activity of the active agent, i.e., the capacity to activate the receptors in the process of the drug-receptor interaction. Compounds that have only an affinity to particular types of receptors without an intrinsic activity will behave as blocking agents. Compounds may greatly differ in their affinity. **Also, the capacity of bioactive agents to activate their specific receptors, the intrinsic activity, may differ for different compounds. These variations result in a differentiation among full agonists, partial agonists, partial antagonists, and full antagonists, which, besides, their affinity to the receptors, display a high, intermediate, low, and zero intrinsic activity, respectively, for the receptors. ** Examples of partial antagonists are the adrenergic blockers with intrinsic sympathomimetic activity. Various aspects of partial agonists and partial antagonists are discussed and elucidated.

3

I concur with Blue Blistering Barnacle.

Not really my area of expertise either; but FWIW I believe it is a slight oversimplification to talk about “a receptor” as something like a Yale lock which is completely uniform so that all people have “the same receptor” which will act in the same way in the presence of a particular drug.

For example this abstract, which I picked pretty much at random, seems to be saying that patient-to-patient variation in response to analgesia may be due to mu receptor polymorphism. I presume the mechanism here is that (in very broad brush) something that is pretty much a full-on agonist on one patient is more like a partial agonist in another, because of subtle patient-to-patient genetic differences in the structure of the receptor.

The overall effect of this is to muddy the waters when it comes to what acts as an agonist, a partial agonist, etc. Here’s the wiki page on pharmacogenomics. It goes beyond receptor polymorphism, but you may still find it interesting.

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