Chapter 2 — Exercises

Items marked † have worked solutions in Appendix M.

A. Recall

2.1 Define ligand and receptor, and state the relationship between them.

2.2 † Why is "induced fit" a better description of binding than "lock and key"? Give two distinct reasons.

2.3 How many times does a GPCR span the cell membrane?

2.4 Name the second messenger most commonly produced downstream of a GPCR, and the enzyme that makes it.

2.5 † List the four mechanisms by which the body terminates a peptide signal, and state which two a drug designer can engineer around.

2.6 Define autocrine, paracrine, and endocrine signaling.

2.7 What is a neuromodulator, and how does it differ from a classical neurotransmitter?

2.8 Define desensitization, downregulation, tolerance, and tachyphylaxis, and state the approximate timescale of each.

B. Distinguishing the five ligand types

2.9 For each, state whether it is an agonist, antagonist, partial agonist, inverse agonist, or biased agonist: (a) binds and fully activates; (b) binds and blocks without activating; (c) binds and reduces activity below the resting baseline; (d) binds and activates only the G-protein arm, not the arrestin arm; (e) binds and activates to 40% of maximum no matter the dose.

2.10 † Explain the counterintuitive property of partial agonists: how can the same molecule act as an activator in one situation and an inhibitor in another? What determines which?

2.11 A -relin compound and a -relix compound act at the same receptor. Using Chapter 2's vocabulary, state what each is.

C. Affinity, potency, efficacy

2.12 † Two compounds both produce a maximum 100% response, but compound A requires one-tenth the concentration of compound B. Which property differs? Which is the same?

2.13 A compound binds its receptor extremely tightly and produces no cellular response at all. Name the property that is high and the property that is zero, and classify the compound.

2.14 Sketch (or describe) three dose-response curves: a potent full agonist, a less potent full agonist, and a partial agonist. Label which axis shift represents potency and which represents efficacy.

2.15 † A product page states: "Our peptide has 30× the receptor binding affinity of the natural hormone." Write three questions that this claim does not answer, and explain why each matters more than the affinity figure.

D. "Explain this to a friend"

2.16 † Explain, in four sentences and without the words receptor, cascade, or amplification, how a hormone present in trace amounts can change what an entire organ does.

2.17 Your friend says: "This peptide activates the growth hormone receptor, so it'll help me build muscle." Respond in a way that is accurate, concedes what is true, and does not sound like a lecture.

2.18 Explain why "it stopped working, so I took more" is a specifically bad instinct in peptide pharmacology. Use no technical vocabulary.

E. Applied reasoning

2.19 † A peptide works beautifully as a local paracrine signal in a tissue. A company develops it as an injected systemic drug and it fails. Give three distinct mechanistic explanations for the failure that are consistent with Chapter 2.

2.20 Native GLP-1 has a half-life of one to two minutes. Semaglutide has a half-life of about a week. Using §2.7, explain which termination mechanisms semaglutide defeats and which it does not — and predict a consequence of the ones it does not.

2.21 Selectivity is described in §2.2 as "a statement about concentration, not a property of the molecule." Explain what this means and give the oxytocin/vasopressin example. Then state a practical implication for someone using a compound at an unstudied dose.

2.22 † Insulin therapy for type 1 diabetes does not lose effect over decades. GLP-1 receptor agonists' nausea fades within weeks while their metabolic effects persist. Explain both observations using §2.8, and extract the general principle.

2.23 A researcher reports that a peptide "restores youthful signaling in aged cells." Using §2.9, identify which of the seven steps this claim has evidence for and which it does not.

F. Identify the red flags

2.24 A marketing page states: "Clinically shown to activate the receptor 3× more effectively than the natural peptide, with sustained activation for 24 hours." Identify at least four things this sentence does not establish. Note especially what "clinically" is doing.

2.25 † A supplement claims its ingredient "modulates cellular signaling pathways to optimize recovery." Rewrite the claim as specifically as the evidence would have to be to support it, then state what each added specification would require somebody to have measured.

G. Judgment

2.26 §2.9 argues that mechanism is "strong evidence against, weak evidence for." Explain the asymmetry in your own words. Then construct the best counterargument you can — a case where mechanistic reasoning should substantially raise your confidence that something works.

2.27 † Biased agonism was designed to separate a drug's benefits from its harms by triggering some downstream pathways and not others. Several such programs have disappointed. Does that failure undermine the concept, undermine its application, or neither? Argue a position and state what evidence would settle it.

2.28 A friend argues: "You keep saying mechanism isn't evidence, but every drug that works has a mechanism. So mechanism must matter." Identify the logical error, and explain it without condescension.

H. Evidence Dossier extension

2.29 † Complete Field 3 (Mechanism) for every peptide in your dossier. Write the plain-language sentence first. Where a receptor is not established, write "not established" — do not guess.

2.30 Pick the peptide in your dossier you are most confident about. Write out the seven-step chain from §2.9 and mark each step E (evidence exists), A (assumed), or U (unknown). Count your E's. Write one paragraph on what you found.

2.31 Now do the same for the peptide you are least confident about. Compare the two step-charts. Is the difference in the number of E's, or in which steps have them? What does that tell you?