Pharmacology · Receptor biology · continued

Receptor desensitisation as a tolerance hypothesis, and its weak evidence — the long version posts 61–64

Pharmacology › Receptor biology retatrutide amylin analogues semaglutide

This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.

GDashwoodTL3Regular16 Jan 2026#61

ne.laurent, post #51: Post #49 and I disagree about the size of the effect, not about the direction. 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 confident version of… Go to post

Taking post #58 at face value and following it one step further.

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.

Reading it again, the caveat matters more than the finding.

4 likes in reply to #51 6mo

coldchain_liuTL3Regular17 Jan 2026#62

Long-term receptor changes: very little is known about what happens to receptor expression, signalling, and downstream effects over years of exposure to these compounds. That is exactly the knowledge gap phase 3 trials exist to fill.

12 likes 6mo

v.klausenTL3Regular17 Jan 2026#63

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.

0 likes 6mo

s.solbergTL218 Jan 2026#64

Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.

0 likes 6mo

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Receptor desensitisation as a tolerance hypothesis, and its weak evidencePharmacology › Receptor biology · 57 replies

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