A Textbook of Clinical Pharmacology and Therapeutics

AGONISTS 7

Receptors were originally classified by reference to the relative
potencies of agonists and antagonists on preparations contain-
ing 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-receptor-
mediated responses, such as vasoconstriction in resistance
arteries supplying the skin. Quantitative potency data are best
obtained from comparisons of different competitive antag-
onists, as explained below. Such data are supplemented, but not
replaced, by radiolabelled ligand-binding studies. In this way,
adrenoceptors were divided first into αandβ, then subdivided
intoα 1 /α 2 andβ 1 /β 2. Many other useful receptor classifications,
including those of cholinoceptors, histamine receptors, sero-
tonin 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 classifi-
cations 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 ner-
vous system – raising hopes for novel drugs targeting these.

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 acti-

vation 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.

salbutamolis 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 depolariza-

tion 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).

0

0

510

100

Effect (%)

(a) [Drug]

1 10 100

100

Effect (%)

(b) [Drug]

Figure 2.2:Concentration/dose–response curves plotted (a) arithmetically and (b) semi-logarithmically.

1

0

10 100

100

Effect (%)

[Drug]

A B

C

Figure 2.3:Concentration/dose–response curves of two full
agonists (A, B) of different potency, and of a partial agonist (C).