Why Intracellular Drugs May Hold the Key to GPCR Therapeutics

Terry's Desk
Aug 5
3 min read

Updated: Aug 11

Kenakin’s latest lecture delivers a game-changing framework for teams grappling with the gap between in vitro potency and in vivo performance, especially when target engagement doesn't explain clinical outcomes.

This lecture is a guide to understanding why intracellular drug access changes everything: from target residence time to diffusion-driven pharmacodynamics and the discovery of previously untargetable sites.

In this session, you’ll gain:

✅ A clear breakdown of how intracellular vs. extracellular receptor access alters diffusion, offset kinetics, and rebinding

✅ Real-world examples of how residence time—not potency—predicts therapeutic coverage

✅ Insight into cryptic intracellular GPCR sites, including allosteric modulators only accessible from inside the cell

✅ Tools for evaluating scaffold permeability using modern, cost-effective pharmacokinetic assays

Why Intracellular GPCR Drugs Change the Game

For decades, drug design has treated GPCRs as surface targets. And while that strategy has yielded enormous success, it ignores a powerful reality: the cytosol is a restricted diffusion compartment. Once a ligand crosses into this intracellular space, it behaves differently, often much more favorably.

Offset slows. Rebinding becomes possible. And intracellular targets, including allosteric sites unreachable from the extracellular side, become available.

In this protected environment, pharmacokinetics can decouple from plasma clearance. You get longer activity with shorter exposure—a dream scenario for drug designers. Kenakin walks you through the science, the data, and the practical methods for making it happen.

Restricted Diffusion, Rebinding, and Residence Time: The Hidden Variables

One of the most actionable takeaways from this lecture is how intracellular environments create the conditions for kinetic persistence. This isn’t just theoretical—Kenakin shows data from risperidone, comparing offset rates in open compartments vs. restricted ones like the brain.

When a drug rebounds after dissociating—something only possible in a diffusion-limited space—it can maintain target occupancy long after systemic levels drop. These aren’t small differences. They’re the reason two equipotent drugs may perform very differently in vivo.

You’ll learn how to recognize and harness this in your own programs.

Same Affinity, Different Outcomes: Why Residence Time Matters More

Two ligands. Identical in vitro affinity. One with rapid offset, the other with slow offset.

In a traditional assay, they look the same. But in vivo? The slow-offset compound stays on target longer, maintains therapeutic effect as concentrations drop, and achieves better real-world outcomes.

Kenakin shows how this plays out in model systems and clinical data—and why residence time should be a first-class design parameter, not an afterthought.

New Tools for Getting Drugs Inside Cells

All of this hinges on a simple question: can your compound get inside the cell?

The good news: we now have reliable, low-cost assays to find out —Kenakin walks through the essential methods to assess intracellular access and permeability.

He also reviews key scaffold properties that determine success, offering practical tips for design teams to tune drug-like balance between lipid and aqueous environments.

GPCRs Aren’t Just Surface Receptors Anymore

From β2-adrenoreceptors to CCRs and dopamine receptors, multiple GPCRs now have validated intracellular allosteric sites. And while orthosteric ligands may never reach them, properly designed intracellular drugs can.

This opens up a new pharmacological space—and a reason to revisit “failed” targets with fresh eyes.

If your pipeline is built only around extracellular engagement, you might be leaving opportunities untapped.

Persistent binding isn’t just about longer half-lives—it’s about smarter pharmacology.

Intracellular access transforms the kinetic profile of your drug, which may be the difference between success and failure.

Unlock “Intracellular Drugs” Now

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Weekly deep dives from Dr. Terry Kenakin
Monthly Ask‑Me‑Anything sessions with live Q&A
An expanding on‑demand library of past lessons
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Whether you’re in discovery, refining SAR, or steering strategy, this is the one place where 40 years of GPCR experience is distilled into practical insight.

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