The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors

Background and PurposeThe classical theory of receptor action has been used for decades as a powerful tool to estimate molecular determinants of ligand‐induced receptor activation (i.e., affinity and efficacy) from experimentally observable biological responses. However, it is also a well‐recognized fact that the receptor‐binding and activation mechanisms, and the parameters thereof, described in the classical theory contradict with the modern view of receptor activation based on allosteric principles.Experimental ApproachWe used mathematical analysis, along with some numerical simulations, to answer the key question as to what extent the classical theory is compatible—if at all—with the modern understanding of receptor activation.Key ResultsHere, we showed conclusively that (1) receptor activation equations based on allosteric principles contain the logic of the classical theory in disguise, and therefore, (2) estimates of “intrinsic efficacy” (ε) obtained by means of classical techniques (i.e., null methods or fitting the operational model to concentration‐response data) are equivalent to the allosteric coupling factors that represent the molecular efficacy of ligands.Conclusion and ImplicationsThus, we conclude that despite the justified criticisms it has received so far, the classical theory may continue to be useful in estimating ligand efficacy from experimental data, if used properly. Here, we also provide rigorous criteria for the proper use of the theory. These findings not only have implications for ligand classification but also resolve some long lasting discussions in the field of bias agonism in GPCR, which requires reasonable estimates of relative ligand efficacies at different signalling pathways.

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect as agonist's efficacy

Onaran,

Costa

2024

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24 (Alexander, Christopoulos et al, 2023;Alexander, Fabbro et al, 2023).…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long‐acting dual amylin and calcitonin receptor agonist improves insulin‐mediated glycaemic control and controls body weight

Melander,

Larsen,

Karsdal

et al. 2024

Background and PurposeInsulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half‐life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D.Experimental ApproachSprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg−1) to induce T1D. Humulin (1 U/200 g·day−1 or 2 U/200 g·day−1) was continuously infused, while half of the rats received additional KBP‐336 (4.5 nmol·kg−1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study.Key ResultsTreatment with Humulin or Humulin + KBP‐336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP‐336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin‐treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta‐cell preservation.Conclusion and ImplicationsThe insulin sensitizer KBP‐336 lowered glucagon secretion while attenuating insulin‐induced weight gain. Additionally, KBP‐336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24 (Alexander et al, 2023).…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Characterisation of cotadutide's dual GLP‐1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model

Bosch,

Petrone,

Arends

et al. 2024

Background and PurposeCotadutide is a dual GLP‐1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP‐1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585).Experimental ApproachThe cotadutide PK‐4GI systems model was calibrated to clinical data by re‐estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP‐1 and glucagon receptor agonistic effects on glucose.Key ResultsCotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP‐1 receptor‐mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200‐μg cotadutide dose.Conclusion and ImplicationsThe 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP‐1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds.