Orthosteric vs Allosteric Interactions— and the pHSense Shift in Internalization

Dr. GPCR News
Oct 2
5 min read

This week’s edition links ligand mechanism to the decisions that shape affinity, efficacy, selectivity, safety, and downstream assays.

Welcome to this week’s Dr. GPCR Weekly News Free Edition—your clear, credible signal in a noisy field.

Each week we highlight the decisions that move GPCR projects forward—from pharmacology essentials to ligand binding site strategies, bench-ready tools, and industry momentum shaping GPCR pipelines.

Read fast, apply faster, and stay ahead in GPCR drug discovery with evidence-based insights—no hype, just strategies you can use.

Breakthroughs this week: New work clarifies how active-state GPCR conformations can support coupling to multiple transducers; plus obesity-drug program milestones and company pipeline updates.

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Industry insights: Fresh selectivity datasets on openMe; Novo’s obesity dominance faces new challengers; integrating AI + structure + throughput to accelerate GPCR programs; key psychiatry and obesity updates and a noteworthy oncology first-in-patient milestone.

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Must-read publications: Studies on active-state GPCR ensembles and their transducer coupling, biased angiotensin receptor ligands, and circuit-selective analgesia in pain models.

Terry's Corner – Orthosteric vs. Allosteric Interactions

When should you push the native system—and when should you partner with it?

This week in Terry's Corner, we focuse on the distinction between orthosteric and allosteric mechanisms and the impact of this choice on affinity, efficacy, safety, and downstream decision-making.

If your team is arguing about “potency vs. effect size vs. duration,” this is your playbook for aligning strategy with biology and avoiding preventable rework.

You’ll learn how to:

Solve the override vs. finesse dilemma: When orthosterics hijack the signal vs. when allosterics fine-tune (and why that matters for target exposure and safety).
Win on kinetics, not just Kd: Dynamic binding means “affinity” moves—design readouts and decisions that respect receptor state lifecycles.
Separate effect size from time: Use allosteric modulators to expand therapeutic index and reduce overdose risk without sacrificing meaningful efficacy.

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Inside Revvity's R&D: How pHSense Was Born

The day your data surprises you—in the best possible way—is the day you know you’re onto something.

For Dr. Eric Trinquet and his team at Revvity, that moment came when they watched GPCRs internalize in native beta cells—without engineered tags, radioactive tracers, or complex imaging setups. Instead, the signal came clean, scalable, and unmistakably real.

It wasn’t luck. It was persistence.

Years of chemistry, photophysics, and pharmacology condensed into one breakthrough: pHSense, a reagent designed to make receptor trafficking visible in the systems that matter most.

From Bench Frustrations to Breakthrough Design

For decades, GPCR trafficking research relied on overexpression and fluorescent imaging—powerful, yes, but far from physiological.

The Revvity team asked a harder question: What if you could measure receptor internalization in native cells, without distorting biology?

The answer was anything but straightforward. Rare-earth europium complexes offered potential—but the chemistry was brutal. Solubility issues, fragile photophysical properties, endless false starts.

That’s where collaboration came in.

Working closely with Professor David Parker of Durham University, Trinquet’s group cracked the scaffold.

By carefully tuning both brightness and fluorescence lifetime, they engineered a two-dimensional pH response: probes that get brighter and glow longer as receptors descend into acidic endosomes.

“You’re not changing the spectrum,” Trinquet explains. “You’re changing how bright it is—and how long it glows.” That subtle distinction opened the door to a brand-new assay format.

Why It Matters

Instead of imaging-heavy workflows, pHSense offers a no-wash, plate-reader–ready, high-throughput assay that finally connects internalization readouts with physiological relevance.

Available in four formats, it turns a notoriously tricky measurement into something discovery teams can actually scale—without sacrificing biological fidelity.

And perhaps that’s the deeper story: Revvity’s R&D team didn’t just invent another tool. They translated a fundamental principle of chemistry into a usable platform for pharmacology—showing how persistence, precision, and the courage to take on “impossible” chemistry can shift the entire GPCR toolkit.

👉 Go behind the scenes with Revvity’s R&D team ➤

Celtarys Research – Advantages of Fluorescent Ligands in CNS GPCR Drug Discovery

In neuroscience drug discovery, the right tool can be just as critical as the right target. For GPCRs, fluorescent ligands have quietly become one of the most versatile technologies—supporting everything from hit validation to pre-clinical assays.

Why? Because they give researchers something rare in CNS work: clarity in complexity.

The Advantages

Live-cell imaging: visualize receptor–ligand interactions in real time, without disturbing native cell states.
Subtype specificity: selectively track receptor subtypes in complex brain tissue.
Cleaner data: higher signal-to-noise ratios sharpen CNS assays.
Speed: faster GPCR target validation and assay development.
Safety: a non-radioactive alternative, sidestepping regulatory hurdles.

Why It Matters

In the CNS, where receptor localization and real-time signaling shape therapeutic outcomes, fluorescent ligands deliver both precision and adaptability. B

y integrating them into GPCR workflows, discovery teams can accelerate identification, characterization, and lead optimization—reducing noise while increasing confidence in every step.

👉 See how fluorescent ligands sharpen CNS drug discovery ➤

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