Chapter 2 — Further Reading

Tier 1 — Verified canonical

G-protein-coupled receptors. The 2012 Nobel Prize in Chemistry was awarded to Robert J. Lefkowitz and Brian K. Kobilka "for studies of G-protein-coupled receptors." The Nobel Prize organization publishes both lectures and the scientific background document free online. The background document in particular is an unusually good survey of how the field got from "receptors are an inference" to atomic-resolution structures, and it is written for scientists outside the specialty.

Earlier and closely related: the 1994 Nobel Prize in Physiology or Medicine (Alfred G. Gilman and Martin Rodbell) for the discovery of G proteins and their role in signal transduction. The transduction step in §2.3 is theirs.

Receptor pharmacology as a discipline. Rang and Dale's Pharmacology and Goodman & Gilman's The Pharmacological Basis of Therapeutics both treat agonism, antagonism, affinity, potency, efficacy, and dose-response relationships far more rigorously than this chapter. Goodman & Gilman is the standard reference behind this book's pharmacology and is named in the project's reference structure.

The IUPHAR/BPS Guide to Pharmacology (guidetopharmacology.org) is a free, expert-curated database of receptors and their ligands, maintained by the International Union of Basic and Clinical Pharmacology. If you want to know what receptor a compound acts at and what is actually established about it, this is the authoritative free source — and it is dramatically better than a search engine for this specific purpose.

Structural data. The Protein Data Bank (rcsb.org) holds solved GPCR structures, including receptor–G protein complexes. Many entries have accessible summary pages.

Oliceridine. Approved by the FDA in 2020; the complete approved labeling is available free on DailyMed and via Drugs@FDA. Reading the label alongside Case Study 2 is instructive — note which class warnings it carries.

Tier 2 — Attributed, specifics unverified

On GPCRs as drug targets. The frequently cited estimate that GPCRs are the target of roughly a third of approved drugs appears widely in the pharmacology literature. Precise figures vary with how the count is done (by drug, by target, by approval year), which is why this book states it as "roughly a third" rather than a decimal.

On the number of human GPCRs. Commonly given as approximately 800, of which a substantial fraction are sensory (olfactory) receptors, and a meaningful number remain "orphans" whose natural ligand has not been identified.

On attrition in drug development. The proportion of compounds entering human trials that never reach approval is commonly cited as roughly nine in ten, with substantial variation by therapeutic area. This book states it as a proportion rather than a percentage, deliberately.

On biased agonism at the mu-opioid receptor. The proposition that analgesia and respiratory depression are separable by signaling pathway was influential and is now substantially contested. Subsequent work using mice with disrupted arrestin recruitment has produced results inconsistent with the original model, and an alternative interpretation — that apparent bias among these compounds reflects differences in intrinsic efficacy rather than pathway selectivity — has been argued in the pharmacology literature. This is an active disagreement among specialists, not a settled question, and Case Study 2 describes it as such.

On amplification magnitudes. The step-by-step multiplication figures in §2.4 are illustrative orders of magnitude, not measured values for any specific system. Actual amplification varies widely by receptor, cell type, and condition.

Tier 3 — Illustrative and constructed

• All ASCII diagrams in this chapter — the messaging-range figure, the induced-fit sequence, the GPCR cascade, the amplification chain, the dose-response curves, the termination figure, and the seven-step gap — are schematic teaching devices, not to scale, with illustrative magnitudes.
• The Evidence Rating box in §2.9 uses the book's frozen four-line format on a genuine mechanistic claim; the format is the book's own.
• The escalating-dose pattern described in the §2.8 Safety and Risk callout is a composite of commonly described real behavior, not a documented individual case.

If you only read one thing

Look up one of your dossier peptides in the IUPHAR/BPS Guide to Pharmacology.

You will get: the receptor it acts at (if known), what type of receptor that is, what the endogenous ligand is, and — often — an honest note about what is and is not established. It is curated by pharmacologists rather than by whoever ranks highest in a search, and it will frequently be the first time you see a compound described without an adjective.

If your peptide is not in it at all, that is also information. Note it in Field 3 as "not established" and move on. Chapter 5 will tell you what to do with the gap.

Looking ahead

Chapter 3 covers the endocrine axes. The useful background is negative feedback as a control principle — the same idea as a thermostat — and the hypothalamic-pituitary organization. Any physiology textbook covers both; Guyton and Hall's Textbook of Medical Physiology is the standard, and its endocrine chapters are more readable than their reputation suggests.