From receptor selectivity to β-cell function: how to make obesity drugs with stronger translational pharmacology

The pharmacology of obesity drugs is no longer defined by a single receptor model.

In this issue of our LinkedIn newsletter, Lakshmi Anantharaman explores how researchers can strengthen translational pharmacology in obesity drug discovery by evaluating receptor selectivity, signaling pathways, and β-cell function early in development.

“The obesity therapeutic landscape has undergone a remarkable shift from single-target interventions to dual- and triple-receptor agonists designed to control appetite, regulate glucose, and balance energy.” – Lakshmi Anantharaman, Director of Screening, Eurofins Discovery

For the next generation of obesity drugs,

This added complexity changes what early pharmacology assays need to establish. A candidate may activate its intended receptors yet still require optimization of potency and downstream signaling. While these innovative therapeutic approaches offer significant opportunities, they also introduce new development challenges that require more sophisticated pharmacology tools and screening strategies.

For incretin-based programs, two questions are especially useful:

Does the candidate show the intended potency and selectivity profile across relevant receptors?
Does the relevant receptor activity produce a functional response in a human β-cell system?

Addressing these questions early can help R&D teams make more informed decisions during lead optimization and candidate selection.

Why class B GPCR selectivity matters for obesity

Glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GCGR) are key targets for many current obesity programs because they connect insulin secretion, appetite, and overall energy balance. Dual and triple agonists such as tirzepatide and retatrutide, respectively, combine these targets and resulting physiological changes.

GLP-1R, GIPR, and GCGR belong to the Class B secretin family of G protein-coupled receptors (GPCRs). Their shared structural homology and signaling pathways can increase the potential for cross-reactivity, complicating selectivity assessment and downstream development decisions. Profiling a broader Class B GPCR panel can reveal agonist or antagonist activity at related receptors that might be missed when the intended targets are evaluated in isolation.

In addition, when compounds are tested under a common dose-response design, teams can compare:

Potency and maximal response at the intended receptors
Relative activity across the components of a dual or triple agonist
Cross-reactivity with related Class B receptors

Is one measure of potency enough?

In early pharmacology studies, we’re used to looking at EC50 as a measure of potency from functional cell-based and binding assays. But EC50s are assay- and system-dependent, rather than an intrinsic measure of molecular potency. Therefore, using orthogonal assays to reduce technique-specific bias and false positives can build confidence in the potency of a therapeutic candidate.

Orthogonal assays answer different pharmacology questions:

Binding assays estimate receptor affinity without requiring downstream signaling
cAMP assays quantify activation of a G-protein coupled signaling pathway
β-arrestin recruitment assays are proxies for downstream receptor internalization and endocytosis

For obesity candidates designed around a specific balance of GLP-1R, GIPR, and GCGR activity, potency rankings may differ across cAMP, binding, and β-arrestin assays, making orthogonal testing important for defining mechanism.

Signaling bias can further distinguish compounds that activate the same receptor. Willard et al. reported that tirzepatide favors cAMP signaling over β-arrestin recruitment at GLP-1R; operational modeling can assess whether other candidates share this profile.

Connecting incretin signaling to β-cell function

For candidates targeting incretin signaling, receptor pharmacology is only the first step. Because pancreatic β cells integrate glucose metabolism with incretin receptor signaling, their downstream response provides important functional data.

Pairing cAMP and glucose-stimulated insulin secretion (GSIS) assays, therefore asks a more physiological question than receptor activation alone:

Does an investigational compound enhance insulin release under the glucose conditions in which that response should occur?

Let us know in the comments!

GSIS measures glucose-regulatory function, but not appetite, gastric emptying, energy expenditure, nausea, or long-term weight loss. These outcomes require additional cellular and in vivo models.

A strategy for obesity drug development

For obesity therapies, a practical and strategic screening cascade can help build the preclinical evidence needed to forge a path toward the clinic:

Define intended activity by measuring potency and efficacy at the primary obesity targets.
Test receptor-family selectivity by profiling related Class B GPCRs under a common assay design.
Resolve mechanism of action with binding, cAMP, β-arrestin, internalization, or bias analyses as the program requires.
Translate signaling into function by comparing β-cell cAMP responses with glucose-stimulated insulin secretion.
Extend the evidence to broader off-target, safety, appetite, tolerability, and in vivo efficacy studies before candidate selection.

This order helps prevent two common interpretation errors: treating one assay as a complete mechanism and/or assuming that receptor activation alone predicts an obesity-relevant physiological response.

Supporting translational pharmacology in obesity programs

Eurofins Discovery offers complementary capabilities for evaluating receptor pharmacology and downstream β-cell function throughout obesity drug discovery.

The Peptide Hormone Class B GPCR Dose-Response LeadHunter Panel provides 10-point cAMP dose-response profiling across 20 targets in the glucagon, calcitonin, corticotropin-releasing factor, parathyroid hormone, and VIP/PACAP receptor subfamilies. Researchers can use the panel to characterize intended activity, compare the receptor components of multi-agonist candidates, and identify activity at related Class B GPCRs.

The Human β-Cell Glucose-Stimulated Insulin Secretion platform provides separate cAMP and GSIS assays in a physiologically relevant human β-cell system that co-expresses functional GIPR, GLP-1R, and GCGR. This enables direct comparison of receptor-proximal signaling and glucose-dependent insulin secretion within a common cellular background.

These platforms can be integrated with receptor-binding, β-arrestin recruitment, receptor internalization, broader GPCR profiling, translational cellular, and in vivo metabolic studies to build an evidence package aligned with each program’s development questions.

By connecting receptor selectivity, signaling, and β-cell function, researchers can make more informed decisions during lead optimization and candidate selection.

To learn more about how we can support your obesity drug discovery program, visit us: click here early in development.

With over 15 years in in vitro drug discovery, Lakshmi specializes in assay development, GPCR pharmacology, and translational screening. She has led more than 40 high-throughput screening, hit-to-lead, and lead optimization programs, helping clients advance promising candidates through the drug discovery pipeline.