Canonical Question

PD – Drug dose-response

V5 B2.iii Historical V4 C.ii 3 appearances

Master answer

Receptors

Receptor → protein-based moiety that contains a region that binds a natural ligand (or drug) to bring about a response
They are located either:
- Within the cell membrane → ligand is poorly lipid-soluble (Ie. cannot cross cell
  membrane)
- Intracellularly → ligand is lipid-soluble (Ie. can cross cell membrane)
Drug-receptor binding can invoke 3 responses:
- Elicits an effect → agonist response
- Prevent the action of a natural ligand → antagonist response
- Reduce a constitutive effect of a receptor → inverse agonist response
There are 5 classes of receptors:
- Ligand-gated ion channels
- G-protein coupled receptors (GPCR)
- Membrane guanylyl cyclase
- Tyrosine kinase receptors
- Intracellular receptors

Receptor		Structure / Mechanism		Class	Action	Example
Ion channel receptors (ionotropic)	Ligand-gated	– part of membrane-spanning complex of protein subunits that can form a channel through the membrane – generally found in excitable tissue	Ligand (or drug) binds to receptor to regulate ion flow through channel	Pentameric family	Possess 5x membrane-spanning units	nAChR – Na GABA-A receptor – Cl 5-HT3R glycine receptor
				Ionotropic glutamate	Glutamate is an excitatory NT in CNS that acts on various ligand-gated ion channels	NMDA receptor – Ca2+ AMPA, Kainate receptors – Na / K
				Ionotropic purinergic receptors	ATP acts on PX1/PX2 receptors → involved in pain and mechano-sensation	PX1/PX2 receptors – Na,K,Ca – mechanosensation and pain
	Voltage-gated	Have a common 4-subunit structure (each with 6 transmembrane segments) surrounding a central pore This pore is selective for the particular ion	Undergo a conformational change when the threshold potential is reached This is sensed by the S4 helix, which acts to open and close the channel	Na+	Important in generating and transmitting an action potential by permitting sodium influx into cells	Located in myocytes and neurons
				Ca+	L	Muscular contraction
					T	Cardiac pacemaker
					N/P/Q	Neurotransmitter release
				K+	Located in myocytes and important in repolarisation following an action potential.
GPCR (metobotropic)		– Membrane bound protein with serpentine structure – associated with a heteromeric G-protein (α, β, γ subunits – α subunits binds either GTP or GDP) on the intracellular aspect of cell membrane	Ligand (or drug) binds to GPCR extracellularly → induces conformational change that activates G-protein, which triggers a cascade of intracellular signalling mechanisms – Inactive: GDP bound to α subunit, which is associated with a βγ-dimer – Active: G-protein activated by ligand-bound GPRC – GTP replaces GDP → activates or inhibits effortor protein: adenyl cyclase (AC) / phospholipase C (PLC) / ion channel – Intrinsic GTPase in α subunit hydrolyses GTP to GDP → regenerates an α-GDP subunit which reassociates with βγdimer → inactive	Gs	α-subunit activates AC → ↑ cAMP synthesis → cAMP binds protein kinase A (PKA) to produce cellular effect (Ie. ∆ gene transcription, ∆ ion permeability of membrane)	β1, β2, β3 receptors H2 receptor
				Gi	α-subunit inhibits AC → ↓ cAMP synthesis → ↓ PKA activation → cellular effect	α2 receptor M2 and M4 receptors
				Gq	α-subunit activates PLC → cleaves membrane phospholipid (phosphatidylinositol biphosphate; PIP2) into: – Inositol tri-phosphate (IP3) → causes Ca2+ release from ER – Diacylglycerol (DAG) → activates protein kinase C	α1 receptor M1, M3 and M5 receptors H1 receptor
Enzyme-linked receptors (Catalytic)	MONOMER: Membrane guanylyl cyclase	activated by a ligand and cause enzymatic activity on the intracellular side		Membrane-bound receptors a/w an intrinsic guanylyl cyclase	Ligand or drug binds to receptor → activates intrinsic guanylyl cyclase → ↑ cGMP → phosphorylation of IC enzymes → cellular effects	guanylyl cyclase (ANF receptor) Guanylyl cyclase for NA
Enzyme-linked receptors (Catalytic)	DIMER: Tyrosine kinase receptors	activated by a ligand and cause enzymatic activity on the intracellular side		Transmembrane receptor-enzyme complex that consists of – extracellular ligand-binding domain (2x α-subunits) and – membrane-bound domain (2x β-subunits) associated with a cytoplasmic enzyme (Tyrosine kinase)	Ligand or drug binds to the α-subunits (extracellular domains) which causes the β-subunits (membrane-bound domains) to dimerise → IC tyrosine residues on β-subunits are then phosphorylated leading to activation of tyrosine kinase → this phosphorylates various IC proteins that elicits a cellular effect	Fibroblast GF receptor Insulin receptor
Intracellular receptors		act as “ligand-regulated transcription factors”: – receptors reside within the cytoplasm → held in the inactive form by association with inhibitory proteins – Binding of hormone (or drug) induces conformational change that activates receptor (by releasing inhibitory protein) → receptor-ligand complex translocates to nucleus and associates with DNA promoter sequences → alter gene transcription		Ligands acting on these receptors are lipid soluble → cross cell membrane and bind to receptors within the cytoplasm		Steroid Receptor Superfamily which include steroids, sterols, thyroxine, retinoic acid and vitamin D.

Drug – Receptor Response

Agonist:

Defined as a ligand or drug that binds to a receptor and alters the receptor state resulting in a biological response

Antagonist:

Defined as a ligand that binds to a receptor but does not activate it, instead blocking that receptor to a natural agonist

Efficacy:

Defined as the ability of drug to elicit the maximal effect (EMAX) when bound to receptor
Measured by height of plateau phase (or EMAX) in “log dose-response curve” → ↑ height of plateau phase (or EMAX) = ↑ efficacy
It reflects “intrinsic activity” of the drug (Ie. magnitude of effect drug has once bound)
- Full agonists → 100% efficacy (or IA = 1)
- Partial agonists → efficacy b/t 0 and 100% (or 0 < IA < 1)
- Antagonists → 0% efficacy (or IA = 0)
It is vital when selecting drugs (Ie. paracetamol and morphine are both analgesics but with different efficacy)

Potency:

A comparative measure b/t drugs that have the same action on a receptor (Ie. have same log dose-response curve slopes) → refers to the different doses of two drugs needed to produce the same drug effect (Ie. more potent drug evokes a ↑ response at a ↓ dose)
Measured by the EC50 in “log dose-response curve” → ↑ EC50 = ↓ potency
It reflects the “affinity” of the drug for the receptor → ↑ receptor affinity = ↓ KD or ↑ KA = ↑ potency
It is not as vital when selecting drugs (cf. efficacy), as long as the effective dose can be administered conveniently

Pharmacological effect of drug-receptor binding depends on:

Properties of the drug:
- Affinity (Ie. how avidly a drug binds to a receptor)
  → determined by KA or KD of drug (such that ↑ KA or ↓ KD affinity
- Intrinsic activity (IA; Ie. magnitude of effect drug has once bound)
  → drugs have IA b/t 0 and 1 (Nb. inverse agonists have IA b/t -1 and 0)
State of receptor activation:
- Receptors exist in an equilibrium b/t “active form” and “inactive form”, which is altered by the presence of a drug

	Receptor Affinity	Intrinsic Activity	State of receptor activation	Example
Abscence of Drug			Equilibrium favours most receptors being in inactive form
Full Agonist	High	Full (IA=1)	Drug binds receptors → shifts equilibrium towards ALL receptors being in “active form”	phenylephrine or noradrenaline at α1 receptor
Partial Agonist	High	Fractional (0<IA<1)	Drug binds receptors → shifts equilibrium towards a FRACTION of receptors being in “active form”	buprenorphine at μ receptor
Inverse Agonist	High	-ve (full or fractional) (-1=<IA<0)	Drug binds receptors → shifts equilibrium towards ALL or FRACTION of receptors being in “inactive form”	naloxone at μ receptor
Antagonist	High	no (IA=0)	Drug binds to both receptor forms but does not alter equilibrium b/t “active” and “inactive”	Reversible, competitive: NDMR at nAChR Reversible, non-competitive: ketamine at NMDA receptor Irreversible: phenoxybenzamine at α receptor

Exam appearances

Exam	Exact wording	Relationship	Success
2024A Q01	(a) What are receptors (20% of marks)? (b) Discuss the relationship between the properties of a drug and potential receptor response under the following headings (20% of marks each): (i) Agonists (ii) Partial agonists (ii) Inverse agonists (iv) Antagonists	historical_member	—
2025A Q01	(a) Define receptors and provide a brief outline of their classification. (20% of marks). (b) Define the following terms and outline the receptor-drug binding and activation characteristics of each: (i) Agonists (20% of marks). (ii) Partial agonists (20% of marks). (ii) Inverse agonists (20% of marks). (iv) Antagonists (20% of marks).	safe_repeat	33.00%
2022B Q19	What are receptors? (20% marks). Discuss the relationship between the properties of a drug and potential receptor response under the following headings: agonists, partial agonists, inverse agonists and antagonists (80% marks)	historical_member	—