Drug Targets and Receptors: Binding, Activation, and Blocking

Drug targets: the main “places” drugs act

Most drugs produce effects by interacting with a biological target (usually a protein). The major target types are:

• Receptors: proteins that detect a signal (often an endogenous ligand like a hormone or neurotransmitter) and convert it into a cellular response.
• Enzymes: catalysts that speed up chemical reactions; drugs often inhibit them or act as false substrates.
• Ion channels: pores that open/close to control ion flow and membrane potential; drugs can block the pore or change gating.
• Transporters: proteins that move molecules across membranes; drugs can inhibit reuptake or alter exchange.

This chapter emphasizes receptors because many clinically important drugs work by binding to receptors and changing their activity.

Binding is usually reversible: “occupancy” is not the same as “effect”

Reversible binding as an equilibrium

For many drugs, binding to a receptor is a reversible interaction:

Drug (D) + Receptor (R) ⇌ Drug–Receptor complex (DR)

At any moment, some receptors are unbound (R) and some are bound (DR). The fraction bound depends on drug concentration and how tightly the drug binds.

Affinity vs activation (efficacy): two different properties

• Affinity describes how strongly a drug binds to a receptor (how readily it forms DR and how slowly it dissociates). Higher affinity generally means that lower concentrations are needed to occupy receptors.
• Activation (efficacy) describes what the drug does to the receptor once bound: does it turn signaling on, turn it off, or leave it unchanged?

A common misconception is that “strong binding” automatically means “strong effect.” A drug can bind very tightly (high affinity) yet produce no activation (an antagonist), or even reduce baseline activity (an inverse agonist).

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Step-by-step: separating binding from effect in your thinking

1. Ask: does the drug bind the target? (Affinity/occupancy)
2. Ask: what does binding do to receptor activity? (Efficacy: increase, decrease, or no change)
3. Translate receptor activity into physiology (e.g., airway smooth muscle relaxation vs constriction)
4. Predict what happens when two drugs compete (agonist vs antagonist at the same receptor)

Receptors in focus: one consistent example set (β2-adrenergic receptor in the airways)

To keep concepts consistent, we will use the β2-adrenergic receptor on airway smooth muscle as the example receptor. When β2 receptors are activated, airway smooth muscle relaxes, leading to bronchodilation (helpful in asthma/COPD symptoms).

Example drugs in this set:

• Full agonist: albuterol (salbutamol) at β2 receptors → bronchodilation
• Antagonist (blocker): propranolol (nonselective β blocker; blocks β2 among others) → prevents bronchodilation from β2 agonists
• Partial agonist: pindolol (β blocker with intrinsic sympathomimetic activity; partial agonist at β receptors) → weak activation while also blocking stronger agonists
• Inverse agonist: some β blockers behave as inverse agonists at β receptors in certain systems (concept focus: reduce baseline receptor activity below its constitutive level)

Note: the exact classification of a specific β blocker can depend on receptor subtype and experimental conditions; the goal here is to learn the conceptual categories and how they predict outcomes.

Agonists, partial agonists, antagonists, inverse agonists

Full agonist: binds and activates strongly

A full agonist has affinity (it binds) and high efficacy (it activates the receptor to produce a maximal response for that system).

• Example: albuterol binds β2 receptors and increases signaling that relaxes airway smooth muscle → bronchodilation.

Key idea: increasing albuterol concentration increases receptor occupancy and typically increases bronchodilation until a maximum is reached (system-dependent).

Partial agonist: binds and activates, but with a ceiling

A partial agonist has affinity but lower efficacy than a full agonist. Even if it occupies many receptors, it cannot produce the same maximal effect as a full agonist in that tissue.

• Example concept at β receptors: a partial agonist produces some bronchodilation, but less than albuterol would at comparable receptor occupancy.

Clinically important twist: in the presence of a full agonist, a partial agonist can reduce the overall effect by competing for binding sites while providing less activation per bound receptor.

Antagonist: binds but does not activate

An antagonist has affinity but zero efficacy. It occupies the receptor without turning it on, and it prevents agonists from binding.

• Example: propranolol binds β receptors and blocks albuterol’s access to β2 receptors → less bronchodilation than expected from albuterol alone.

Many antagonists are competitive (reversible) at the binding site: higher concentrations of agonist can sometimes overcome the block by outcompeting the antagonist. The practical takeaway is that antagonists often shift the agonist “dose needed” upward.

Inverse agonist: binds and reduces baseline activity

Some receptors have constitutive activity (they signal a little even without ligand). An inverse agonist has affinity and negative efficacy: it stabilizes the inactive receptor state and reduces signaling below baseline.

• Example concept at β receptors: if β receptors show baseline activity in a given tissue, an inverse agonist would decrease that activity, potentially favoring bronchoconstrictive tone compared with a neutral antagonist (conceptual distinction).

Practical point: in many clinical contexts, “antagonist” is used broadly for blockers, but mechanistically it helps to know whether a drug is neutral (pure antagonist) or inverse (reduces baseline).

How the same receptor can yield different outcomes: affinity, efficacy, and tissue context

Two drugs can both bind β2 receptors yet produce different clinical results because:

• Different efficacy: full vs partial vs inverse agonism changes how much signaling occurs per occupied receptor.
• Different affinity: higher-affinity drugs occupy receptors at lower concentrations and can outcompete others.
• Tissue context: receptor density and downstream signaling capacity vary by tissue, changing the observed maximal effect.

When you predict drug effects, keep the sequence clear: concentration → occupancy (affinity) → receptor activity (efficacy) → physiology.

Other common target types (brief, practical orientation)

Enzymes

Enzyme targets are often inhibited to reduce production of a mediator.

• Inhibition: a drug binds an enzyme and reduces its catalytic activity (reversible or irreversible).
• Practical mental model: less enzyme activity → less product → downstream physiological change.

Example pattern (no deep dive): inhibiting an enzyme that makes a constrictor mediator can indirectly promote relaxation.

Ion channels

Ion channels control electrical excitability and smooth muscle tone.

• Pore block: drug physically blocks ion flow.
• Gating modulation: drug changes probability of opening/closing.

Practical mental model: changing ion flow changes membrane potential and calcium entry, which can alter contraction, secretion, or firing.

Transporters

Transporters regulate neurotransmitter levels and solute movement.

• Reuptake inhibition: increases neurotransmitter in synapse.
• Carrier blockade: reduces movement of ions/solutes, altering gradients and cell function.

Practical mental model: blocking a transporter often increases the concentration of its substrate on one side of a membrane, amplifying or prolonging signaling.

Receptor selectivity vs absolute specificity (avoid a common misconception)

Selectivity is relative and dose-dependent

Selectivity means a drug binds (or activates) one receptor subtype more than others at typical concentrations. It does not mean it binds only one target.

• Example idea: a “β2-selective” agonist preferentially activates β2 receptors in the airways at usual doses, but at higher doses it may also activate β1 receptors (e.g., in the heart), leading to unwanted effects.

Specificity is rare in real biology

Absolute specificity would mean the drug interacts with only one target and nothing else. In practice, most drugs have some off-target binding, especially as dose increases or in different tissues.

Step-by-step: how to reason about selectivity clinically

1. Identify the intended receptor subtype (e.g., β2 for bronchodilation).
2. List likely “neighbor” targets (e.g., β1 in heart; β2 in vasculature).
3. Ask what happens as concentration rises (loss of selectivity → off-target effects).
4. Consider patient factors (organ sensitivity, comorbidities, interacting drugs).

Clinical-style mini-cases: predict agonist + antagonist outcomes

Case 1: Albuterol taken after a nonselective β blocker

Scenario: A patient with wheeze uses inhaled albuterol. They recently started propranolol for tremor.

Question: What happens to the bronchodilator response?

• Prediction: The bronchodilation from albuterol is reduced because propranolol occupies β2 receptors without activating them, preventing albuterol from binding effectively.
• Mechanism: competitive antagonism at the same receptor → less receptor activation at a given albuterol dose.

Case 2: Increasing the agonist dose in the presence of a competitive antagonist

Scenario: Same patient as Case 1. The clinician increases the albuterol dose.

Question: Can higher albuterol overcome the blocker?

• Prediction: If the antagonism is competitive and reversible, some effect may be regained by increasing agonist concentration (more competition for binding). However, the response may still be clinically inadequate and side effects may increase due to spillover to other receptors.

Case 3: Partial agonist present with a full agonist at the same receptor

Scenario: A patient is taking a β-blocker with partial agonist activity (conceptual partial agonist at β receptors). They use albuterol for acute symptoms.

Question: What happens compared with albuterol alone?

• Prediction: The partial agonist can blunt albuterol’s maximal bronchodilation by competing for β2 receptor binding while producing less activation per receptor than albuterol.
• Key concept: a partial agonist can behave like an antagonist in the presence of a full agonist.

Case 4: Antagonist given after agonist

Scenario: A patient receives albuterol and improves. Later they take propranolol.

Question: What happens to airway tone?

• Prediction: Bronchodilation diminishes as propranolol competes for β2 receptors and reduces ongoing receptor activation from albuterol.
• Step-by-step reasoning: propranolol binds → fewer receptors available for albuterol → decreased β2 signaling → less smooth muscle relaxation.

Case 5: Inverse agonist concept check (baseline activity)

Scenario: Assume β2 receptors in a given airway model have measurable baseline signaling even without agonist. A drug that is an inverse agonist at β2 is administered.

Question: What happens compared with a neutral antagonist?

• Prediction: The inverse agonist would reduce baseline β2 signaling below its constitutive level, potentially favoring relatively more bronchoconstrictive tone than a neutral antagonist, which would mainly block responses to agonists without changing baseline activity.