The receptor concept

1
The receptor concept
I therefore assumed that the tetanus toxin must
unite with certain chemical groupings in the
protoplasm of cells As these receptors, which
may be regarded as lateral chains of the
protoplasm become occupied by the toxin, the
relevant normal function of this group is
eliminated Paul Ehrlich, from the Nobel
Lecture, 1908
2
Types of drug receptors

• Practically all receptors are proteins
• Enzymes
• Ion channels
• Ligand-gated channels Ion channels that open
  upon binding of a mediator
• Voltage-gated channels Ion channels that are not
  normally controlled by ligand binding but by
  changes in the membrane potential
• Metabolic receptors hormone and
  neurotransmitter receptors that are coupled to
  biochemical secondary messenger / effector
  mechanisms

3
Non-protein drug target sites

• DNA Mainly cytotoxic agents used in cancer
  therapy
• DNA / RNA Antisense oligonucleotides (mostly
  experimental)
• Fluid compartments Osmotically active solutes
• Plasma volume expanders (dextran)
• Osmotically acting diuretic agents (mannitol)
• Laxatives (sodium sulfate obsolete)

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How do drugs affect their receptor proteins?

• Enzymes
• competitive inhibitors enalapril, angiotensin
  convertase
• irreversible (covalent) inhibitors
  acetylsalicylic acid, cyclo-oxygenase
• allosteric inhibitors digoxin, Na/K-ATPase
• Channels and metabolic receptors
• orthosteric agonists, inhibitors, and partial
  agonists
• allosteric agonists or inhibitors
• irreversible (covalent) inhibitors

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Drug-receptor binding
6
Drug-receptor binding
LR / Rtotal
Ligand concentration
7
Competitive vs. irreversible inhibition
L
I
R
RL
RI
L
I
R
RL
RI
8
Competitive inhibition
K
K
K
L
Receptor occupancy


L K
9
Irreversible (covalent) inhibition
10
Competitive and irreversible inhibition of
a-adrenergic receptors phenoxybenzamine vs.
tolazoline
Norepinephrine
Tolazoline
Phenoxybenzamine
11
The mechanism of covalent receptor blockade by
phenoxybenzamine
12
Effects of phenoxybenzamine and tolazoline in a
tissue model
0
0
10 mM
0.4 mM
20 mM
0.8 mM
13
Drug dose-effect relationships (1)

• Examples
• Enzymes observed effect enzyme activity
• Ion channels observed effect ion conductivity

• Examples
• Enzymes observed effect some physiological /
  clinical readout (acetylsalicylic acid /
  cyclo-oxygenase / pain relief)
• Alpha-adrenergic receptor ? IP3 ? ? Ca ? ?
  increased muscle contraction

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Drug dose-effect relationships (2)
Receptor effector
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Drug dose-effect relationships (3)
Weak maximal effect (e.g., influenced receptor is
only a minor player in physiological effect)
Threshold physiological effect only begins at
finite minimum of receptor occupancy
Effect
Effect saturated at sub-maximal receptor occupancy
Occupancy
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Cascades and dose-response characteristics
17
The effect precedes receptor saturation in
cascade systems
Effect
Binding
Example Rat heart contractility and
b-adrenergic receptors 50 response at
1-3 receptor occupancy
EC50
KR
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The effect precedes receptor saturation in
cascade systems
19
The Schild plot A Null method used to
establish sites of action of putative inhibitors
y x - b
20
The Schild plot (2)
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Spare receptors and irreversible inhibition
0 I 22
The slope parameter of concentration-response
curves used as a touchstone for the existence of
spare receptors Naunyn Schmiedebergs Arch
Pharmacol. (1997) 356283-92.
23
The slope parameter of concentration-response
curves used as a touchstone for the existence of
spare receptors Naunyn Schmiedebergs Arch
Pharmacol. (1997) 356283-92.
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Drug potency and efficacy
Efficacy effect at saturating concentration
Observed effect
potency 1 / EC50
EC50
log Drug
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What if drugs that bind to the same receptor
differ in efficacy?
26
The two-state model of receptor activation
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Inhibitors and partial agonists in the
allosteric model
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The two-state model and inverse agonism
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Beneficial and toxic drug effects
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The therapeutic index
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Two-state model of receptor activation