Chapter 2 — Quiz
Twenty-two questions. Answers below — write yours first.
Multiple choice
1. A molecule that binds a receptor is called a:
a) substrate b) ligand c) effector d) cofactor
2. GPCRs span the cell membrane:
a) once b) three times c) seven times d) twelve times
3. The archetypal second messenger produced downstream of many GPCRs is:
a) ATP b) cAMP c) glucose d) sodium
4. Which of these does the cell actually detect when a peptide binds?
a) the peptide entering the cytoplasm b) the peptide's charge c) the receptor's change in shape
d) a rise in extracellular calcium
5. A compound that binds a receptor without activating it, blocking the natural ligand, is a(n):
a) agonist b) antagonist c) partial agonist d) second messenger
6. A partial agonist in the presence of a full agonist will:
a) increase total signaling b) decrease total signaling c) have no effect d) become a full agonist
7. EC50 measures:
a) affinity b) efficacy c) potency d) half-life
8. Which property describes the maximum effect a drug can produce at any dose?
a) affinity b) potency c) efficacy d) EC50
9. Signal amplification means that:
a) the peptide concentration increases inside the cell b) one bound molecule produces many
downstream events c) the receptor becomes more sensitive d) the drug lasts longer
10. Circulating GLP-1 is present at approximately what concentration?
a) molar b) millimolar c) micromolar d) picomolar
11. Receptor downregulation refers to:
a) rapid uncoupling from the G protein b) reduction in the number of receptors on the cell surface
c) degradation of the ligand d) renal clearance
12. Which two termination mechanisms can drug design engineer around?
a) desensitization and downregulation b) degradation and clearance c) clearance and downregulation
d) all four
13. Tachyphylaxis is:
a) an allergic reaction b) rapid tolerance developing within hours or a few doses c) increased
sensitivity over time d) a rapid heartbeat
14. Paracrine signaling means a cell signals:
a) itself b) neighboring cells over short distances c) distant organs via blood d) across a synapse
15. Roughly what fraction of approved drugs act at GPCRs?
a) 5% b) one-third c) two-thirds d) 90%
16. Approximately what fraction of compounds entering human trials never reach approval?
a) one in ten b) three in ten c) half d) nine in ten
Short answer
17. Explain why "selectivity" is a statement about concentration rather than a fixed property of a
molecule. Use oxytocin and vasopressin as your example.
18. State the seven steps between "activates a receptor" and "benefit exceeds harm," and identify
which require a clinical trial.
19. Why does making an agonist longer-lasting not straightforwardly produce a longer-lasting
effect?
20. Explain why insulin does not lose effect over decades of use in type 1 diabetes, while some
peptide therapies develop tolerance in weeks.
Applying the rating discipline
21. §2.9's Evidence Rating box gives a ✅ to a mechanistic claim about GLP-1 receptor agonists.
Explain why that ✅ does not license the statement "GLP-1 agonists are proven to work."
22. A source states: "The mechanism is well established, so the compound must be effective."
Identify the error precisely, and state the one circumstance under which mechanistic reasoning
legitimately settles a question.
Answer key
**1.** b — ligand.
**2.** c — seven times, which is why they are also called seven-transmembrane receptors.
**3.** b — cAMP, produced by adenylyl cyclase.
**4.** c — the receptor's change in shape. The peptide stays outside; the conformational change is
transmitted through the membrane and detected on the intracellular face.
**5.** b — antagonist.
**6.** b — decrease total signaling. It competes for receptors it activates only weakly, so average
activation falls. This is the counterintuitive property in §2.5.
**7.** c — potency.
**8.** c — efficacy.
**9.** b — one bound molecule produces many downstream events, through a multiplicative cascade.
**10.** d — picomolar. Roughly one hormone molecule per trillion water molecules, and enough to change
what an organ does.
**11.** b — reduction in receptor number on the surface, over hours to days.
**12.** b — degradation and clearance. Desensitization and downregulation are decisions the target
cell makes, and no chemical modification of the drug prevents them.
**13.** b — rapid tolerance within hours or a few doses.
**14.** b — neighboring cells over short distances, without entering the bloodstream.
**15.** b — roughly one-third.
**16.** d — roughly nine in ten, and every one of them entered trials backed by a mechanism somebody
believed in.
**17.** Selectivity means a molecule binds one receptor much more readily than another *at the
concentrations reached in practice*. Oxytocin binds its own receptor far more readily than the
vasopressin receptor — but at high concentrations it does bind vasopressin receptors, which is
clinically relevant during high-dose labor induction. Push the dose and selectivity degrades.
Practical implication: "it's selective" is not a safety argument at an unstudied dose.
**18.** (1) binds and activates the receptor; (2) reaches the target tissue in a person; (3) at a
concentration that matters, for long enough; (4) downstream machinery is intact and available;
(5) the system does not fully compensate; (6) the net result changes an outcome a person notices;
(7) benefit exceeds harm. Steps 1–5 are mechanism and can be studied in cells and animals. **Steps 6
and 7 require a clinical trial** and cannot be inferred from the others.
**19.** Because two of the four termination mechanisms are not about the drug at all. Degradation and
clearance can be defeated by chemical modification. Desensitization and downregulation are responses
by the target cell, and a longer-lasting agonist pushes harder on exactly the machinery that shuts the
signal down — so it may cause the cell to stop listening *sooner*.
**20.** Insulin in type 1 diabetes **replaces a signal that is absent**; there is no intact
homeostatic system being overridden, so no counter-regulation is provoked. Therapies that **override
an intact regulated system** recruit compensation — desensitization, downregulation, and
counter-regulatory signaling. The general rule: expect tolerance when you are pushing on a working
system, and expect durability when you are restoring a missing one.
**21.** Because the two are different claims. The ✅ certifies that GLP-1 agonists bind and activate a
characterized GPCR and produce amplified signaling — a mechanistic fact established in cells and
animals. Whether that helps any patient is a clinical claim requiring clinical evidence, and it gets
its own separate rating in Chapter 8. A mechanistic ✅ and a clinical ✅ are different objects, and
conflating them is one of the most common failures in peptide communication.
**22.** The error is treating mechanism as sufficient rather than necessary — ignoring that at least
six further steps must succeed, and that roughly nine in ten compounds with believed-in mechanisms
fail at one of them. The one circumstance where mechanistic reasoning legitimately settles a question
is **in the negative**: if a mechanism is physically impossible — an unmodified peptide surviving
digestion intact, a large molecule crossing an intact blood-brain barrier unaided — that rules a claim
out with high confidence. Mechanism is strong evidence against and weak evidence for, and the
asymmetry exists because it takes one broken step to stop a chain and all seven to complete one.