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: I read post #49 twice before replying, because I had assumed the opposite. 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. Go to post

This follows post #58 rather than contradicting it.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

4 likes in reply to #51 6mo

coldchain_liuTL3Regular17 Jan 2026#62

Species differences: rodent studies show the same compounds produce effects in rodents that predict human effects reasonably well for semaglutide and tirzepatide. The track record is less clear for novel compounds with less human data.

12 likes 6mo

v.klausenTL3Regular17 Jan 2026#63

Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.

0 likes 6mo

s.solbergTL2 Moderator18 Jan 2026#64

Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.

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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