A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

AGONISTS 7
100
100
Effect (%)
Effect (%)
0
0
5 10
[Drug]
1 10 100
[Drug]
(a)
(b)
Figure 2.2: Concentration/dose–response curves plotted (a) arithmetically and (b) semi-logarithmically.
100
Effect (%)
0
1
A
B
10 100
[Drug]
Figure 2.3: Concentration/dose–response curves of two full
agonists (A, B) of different potency, and of a partial agonist (C).
Receptors were originally classified by reference to the relative
potencies of agonists and antagonists on preparations containing
different receptors. The order of potency of isoprenaline
adrenaline noradrenaline on tissues rich in β-receptors, such
as the heart, contrasts with the reverse order in α-receptormediated
responses, such as vasoconstriction in resistance
arteries supplying the skin. Quantitative potency data are best
obtained from comparisons of different competitive antagonists,
as explained below. Such data are supplemented, but not
replaced, by radiolabelled ligand-binding studies. In this way,
adrenoceptors were divided first into α and β, then subdivided
into α 1 /α 2 and β 1 /β 2 . Many other useful receptor classifications,
including those of cholinoceptors, histamine receptors, serotonin
receptors, benzodiazepine receptors, glutamate receptors
and others have been proposed on a similar basis. Labelling
with irreversible antagonists permitted receptor solubilization
and purification. Oligonucleotide probes based on the deduced
sequence were then used to extract the full-length DNA
sequence coding different receptors. As receptors are cloned
and expressed in cells in culture, the original functional classifications
have been supported and extended. Different receptor
subtypes are analogous to different forms of isoenzymes, and a
rich variety has been uncovered – especially in the central nervous
system – raising hopes for novel drugs targeting these.
C
Despite this complexity, it turns out that receptors fall into
only four ‘superfamilies’ each linked to distinct types of signal
transduction mechanism (i.e. the events that link receptor activation
with cellular response) (Figure 2.4). Three families are
located in the cell membrane, while the fourth is intracellular
(e.g. steroid hormone receptors). They comprise:
• Fast (millisecond responses) neurotransmitters (e.g.
nicotinic receptors), linked directly to a transmembrane
ion channel.
• Slower neurotransmitters and hormones (e.g. muscarinic
receptors) linked to an intracellular G-protein (‘GPCR’).
• Receptors linked to an enzyme on the inner membrane
(e.g. insulin receptors) are slower still.
• Intranuclear receptors (e.g. gonadal and glucocorticosteroid
hormones): ligands bind to their receptor in cytoplasm and
the complex then migrates to the nucleus and binds to
specific DNA sites, producing alterations in gene
transcription and altered protein synthesis. Such effects
occur over a time-course of minutes to hours.
AGONISTS
Agonists activate receptors for endogenous mediators – e.g.
salbutamol is an agonist at β 2 -adrenoceptors (Chapter 33).
The consequent effect may be excitatory (e.g. increased
heart rate) or inhibitory (e.g. relaxation of airway smooth
muscle). Agonists at nicotinic acetylcholine receptors (e.g.
suxamethonium, Chapter 24) exert an inhibitory effect
(neuromuscular blockade) by causing long-lasting depolarization
at the neuromuscular junction, and hence inactivation of
the voltage-dependent sodium channels that initiate the action
potential.
Endogenous ligands have sometimes been discovered long
after the drugs that act on their receptors. Endorphins and
enkephalins (endogenous ligands of morphine receptors)
were discovered many years after morphine. Anandamide is a
central transmitter that activates CB (cannabis) receptors
(Chapter 53).