Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
I have said this before in a thread nobody could find, so it is worth repeating.
19 likes 18mo
Pharmacology · Receptor biology · continued
Biased agonism: a real phenomenon, an over-used explanation — what changed since posts 31–57
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Cross-reactivity at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general.
2 likes 18mo
dr_bhattacharya, post #33: Cross-reactivity at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general. Go to post
Same experience here, different supplier, so it is at least not unique to one of them.
Collapsed as off-topic by two members at trust level 3 or above
Post #33 is right about the mechanism and I think understates the practical bit.
Two claims get bundled together under Biased agonism and they need separating. The descriptive one — this is what was observed — is usually well supported. The causal one — this is why — usually is not.
Almost every disagreement in threads like this one dissolves once you say which of the two you are making.
Coming back to post #32, because the follow-up matters more than the original answer.
Biased agonism — where different ligands at the same receptor favour different downstream pathways — is a plausible explanation for differences between compounds in this class and is not a demonstrated one for any specific pair.
I have no interest in any supplier named above.
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d.vukovic, post #32: I read post #28 twice before replying, because I had assumed the opposite. The most useful thing anyone has posted about Biased agonism in this category was a table of what had been measured and by whom. That is what I would want again. Go to post
GIP receptor biology is genuinely contested. Both agonism and antagonism have been argued to produce weight reduction, and the fact that the field can hold both positions tells you how open it is.
I would put this at better than even and not much better.
k.farrugia, post #4: Summarising the Biased agonism thread so far, since it is long and the answer is buried: the first reply has the method, the fourth has the correction to it, and the rest is people agreeing at length. Go to post
Glucose dependence is the property that distinguishes incretin-mediated insulin secretion from a sulfonylurea. It is also why hypoglycaemia risk from these compounds alone is low.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
citation_peak, post #21: Answering the question post #19 raises rather than the one it answers. Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds. A… Go to post
Agreed on all of that, and I have nothing to add to it.
I have no financial interest in anything named in this thread and I want to say so before I comment on Biased agonism, because it is the sort of subject where it matters.
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g.haaland, post #11: The most useful reply I ever got about Biased agonism was a request to state my units. It sounds like pedantry and it has saved me twice. Go to post
On post #41 — agreed on the reasoning, with one qualification.
GIP receptor signalling: the glucose-dependent insulinotropic peptide receptor (GIP) is involved in glucose-stimulated insulin secretion. GIP agonism is thought to contribute to tirzepatide's effect but the mechanism is not fully settled.
Picking up post #41: that is the part I would want checked first.
Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised.
The reasoning is more useful than the number, which is why I have shown it.
0 likes 18mo
lc_gradient, post #31: Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly. I have said this before in a thread nobody could find, so it is worth repeating. Go to post
Confirming post #45 from a second method, which matters more than confirming it from a second person.
Biased agonism — where different ligands at the same receptor favour different downstream pathways — is a plausible explanation for differences between compounds in this class and is not a demonstrated one for any specific pair.
Post #45 describes the usual case. This is about the unusual one.
The version of Biased agonism that circulates here is a simplification of a simplification. It is not wrong, but it has lost the conditions under which it holds, and those conditions are where the interesting cases live.
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Receptor occupancy required for a clinical effect is not the same as full occupancy, and dose-response curves flattening at the top is what you would expect from that.
A single observation, in a thread that deserves better than single observations.
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Where I part company with post #45, and it is a narrow parting.
Taking Biased agonism seriously for a moment rather than deflecting: the honest position is that the community has observations and no controlled comparison, and those two things support very different sentences.
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bac_water, post #39: Agreed on all of that, and I have nothing to add to it. Go to post
Post #49 is the version of this I will quote in future. One addition.
Ghrelin receptor agonism drives growth hormone release in pulses and also increases appetite, which is the effect people most reliably report and least often want.
The confident version of this sentence would be wrong, so here is the hedged one.
h.krastev, post #47: Post #45 describes the usual case. This is about the unusual one. The version of Biased agonism that circulates here is a simplification of a simplification. It is not wrong, but it has lost the conditions under which it holds, and those conditions are where the interesting cases live. Go to post
The useful distinction on Biased agonism is between what was measured and what was inferred from it. Both end up in the same sentence and only one of them has error bars.
Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.
Happy to be the one who is wrong here if it settles the question.
0 likes 17mo
i.guerrero, post #38: Glucose dependence is the property that distinguishes incretin-mediated insulin secretion from a sulfonylurea. It is also why hypoglycaemia risk from these compounds alone is low. Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki. Go to post
Post #50 describes the usual case. This is about the unusual one.
The C-cell finding in rodent toxicology is a receptor-biology observation with a species-specific interpretation. It is the reason for a specific contraindication rather than a general concern.
Noting that I have skin in this question and have tried to discount for it.
Fine by me. I had wanted a stronger conclusion and there is not one available.
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Practical note on Biased agonism: write down what you expect before you look. The number of times I have found what I went looking for is higher than chance would allow.
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Cross-reactivity at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general.
I am aware this is the third time this month I have made this point.
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This topic was referenced in
- About the Receptor biology categoryPharmacology › Receptor biology · 10 replies
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