🤝 Webinar in collaboration with: Eurofins DiscoverX
Tuning GPCR System Sensitivity: Revealing True Drug Activity Through Functional Volume Control
The pharmacology of a drug is shaped not only by the molecule but by the sensitivity of the system it is measured in. Receptor density and coupling efficiency change what a ligand appears to do, which is part of why in vitro results do not always translate in vivo. This session presents functional volume control, the deliberate tuning of system sensitivity, as a way to separate a ligand's true affinity and efficacy from the system it was tested in.
Dr. Terry Kenakin will show how reducing sensitivity lets you measure affinity and relative efficacy and turn low-efficacy agonists into measurable antagonists, how increasing sensitivity uncovers efficacy hidden in apparently neutral compounds, and how greatly increasing it reveals inverse agonism through constitutive activity. The same approach distinguishes what an allosteric modulator does to affinity versus efficacy, including PAM-agonism. Examples run across inducible, low, and medium expression systems.
Why System Sensitivity Changes What You Measure
The response to an agonist depends on its concentration and efficacy, and on the system: how many receptors are present and how well they couple to their effectors. Two assays with different sensitivities can report different behavior for the same molecule. Treated as a variable to control for, that is noise. Set on purpose, it becomes a measurement tool.
From the Assay to the Candidate
Reduce sensitivity and affinity separates from efficacy, so system-independent values can be measured and used to predict behavior elsewhere. Raise it and low-level efficacy that would drive agonism in a sensitive tissue becomes visible. Raise it further and inverse agonism appears where a calcium assay would have called the compound a neutral antagonist. Each setting answers a different question about a real candidate.
Speaker
Dr. Terry Kenakin
Professor of Pharmacology and Pharmacology Course Coordinator
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill
Head Instructor, Terry's Pharmacology Corner
Dr. Kenakin trained in chemistry and pharmacology at the University of Alberta and completed postdoctoral work at University College London in the laboratory of Sir James Black. He spent 25 years in drug discovery at Glaxo, now GlaxoSmithKline, before joining UNC Chapel Hill, where he teaches and leads research in receptor pharmacology.
His work is central to the quantitative framework used today to describe receptor signaling bias, allosteric function, and agonism. He proposed one of the first mechanistic explanations of biased signaling and co-authored the widely applied simple method for quantifying functional selectivity. He is the author of A Pharmacology Primer, Editor-in-Chief of the Journal of Receptors and Signal Transduction, and a Fellow of the British Pharmacological Society, recognized with the Goodman and Gilman Award from ASPET and the Gaddum Memorial Award.
Within the Dr. GPCR ecosystem, he is Head Instructor of Terry's Corner, a space for live AMAs, short-form mechanistic discussions, and ongoing dialogue with the GPCR community on receptor theory, biased signaling, and the decisions that shape real drug discovery programs.
Organizers
Eurofins DiscoverX
Eurofins DiscoverX is a one-stop-shop for GPCR drug discovery and development, with 25+ years of expertise and validated cell-based assays spanning basic research through therapeutic discovery, optimization, and regulatory submission. Their assays are industry-standard, accepted for regulatory potency testing, and backed by thousands of peer-reviewed publications and partnerships with leading pharma and biotech companies.
>1,500 human GPCR products covering ~90% of the GPCR-ome, including orphan receptors and ortholog variants
Multiple mechanisms of action: cAMP accumulation, β-arrestin recruitment, receptor internalization, ligand binding, calcium flux, pharmaco-chaperone discovery
Flexible formats: cell line assay kits, ready-to-use eXpress kits, qualified bioassays, membrane preps, detection kits, and custom products
Applications across target identification, HTS, lead optimization, ligand bias and allostery evaluation, safety assessment, and regulatory potency testing
Dedicated portfolio for obesity and diabetes GPCR targets (GLP-1R, GIPR, GCGR, MC4R, AMY receptors, and more)
Dr. GPCR
Dr. GPCR is a membership-based nonprofit ecosystem dedicated to advancing GPCR-targeted drug discovery. It provides curated industry intelligence, expert-led masterclasses, and structured engagement opportunities for scientists and biotech leaders working across pharmacology, translational research, and therapeutic development.
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