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Lectures R. GosensGeneral Principles
How drugs act: general principles
▪ One of the basic tenets of pharmacology is that drug molecules must exert some
chemical influence on one or more cell constituents to produce a pharmacological
response.
- drug molecules must get so close to these constituent cellular molecules that the
two interact chemically in such a way that the function of the latter is altered.
PROTEIN TARGETS FOR DRUG BINDING
▪ Four main kinds of regulatory protein are commonly involved as primary drug targets,
namely:
- Receptors
- Enzymes
- Carrier molecules (transporters)
- Ion channels
- Plasma proteins
DRUG RECEPTORS
WHAT DO WE MEAN BY RECEPTORS?
▪ ‘Receptor’ is sometimes used to denote any target molecule with which a drug molecule
(i.e., a foreign compound rather than an endogenous mediator) must combine to elicit
its specific effect.
▪ In the more general context of cell biology, the term receptor is used to describe various
cell surface molecules (such as T-cell receptors, integrins, Toll receptors, etc;) involved in
the cell-to-cell interactions that are important in immunology, cell growth, migration
and differentiation, some of which are also emerging as drug targets. These receptors
differ from conventional pharmacological receptors in that they respond to proteins
attached to cell surfaces or extracellular structures, rather than to soluble mediators
RECEPTORS IN PHYSIOLOGICAL SYSTEMS
▪ Adrenaline first binds to a receptor protein (the β 1 adrenoceptor) that serves as a
recognition site for adrenaline and other catecholamines.
- When it binds to the receptor, a train of reactions is initiated, leading to an increase
in force and rate of the heartbeat. In the absence of adrenaline, the receptor is
normally functionally silent.
▪ There is an important distinction between agonists , which ‘activate’ the receptors,
and antagonists , which combine at the same site without causing activation, and block
the effect of agonists on that receptor.
,DRUG SPECIFICTY
▪ For a drug to be useful as either a therapeutic or a scientific tool, it must act selectively
on particular cells and tissues.
- it must show a high degree of binding site specificity.
- Conversely, proteins that function as drug targets generally show a high degree of
ligand specificity; they bind only molecules of a certain precise type.
▪ The principles of binding site and ligand specificity can be clearly recognised in the
actions of a mediator such as angiotensin
- This peptide acts strongly on vascular smooth muscle, and on the kidney tubule, but
has very little effect on other kinds of smooth muscle or on the intestinal
epithelium.
▪ no drug acts with complete specificity.
▪ the lower the potency of a drug and the higher the dose needed, the more likely it is
that sites of action other than the primary one will assume significance.
- In clinical terms, this is often associated with the appearance of unwanted ‘off-
target’ side effects, of which no drug is free.
▪ ‘On-target’ side effects are unwanted effects mediated through the same receptor as the
clinically desired effect, for example constipation and respiratory depression by opioid analgesic
drugs, whereas ‘off target’ side effects are mediated by a different mechanism.
DRUG-RECEPTOR INTERACTIONS
▪ Occupation of a receptor by a drug molecule may or may not result in activation of the
receptor. By activation, we mean that the receptor is affected by the bound molecule in
such a way as to alter the function of the cell and elicit a
tissue response.
▪ Binding and activation represent two distinct steps in the
generation of the receptor-mediated response by an
agonist ( Fig. 2.1 ).
▪ If a drug binds to the receptor without causing activation
and thereby prevents the agonist from binding, it is
termed a receptor antagonist .
▪ The tendency of a drug to bind to the receptors is
governed by its affinity , whereas the tendency for it, once bound, to activate the
receptor is denoted by its efficacy
▪ Drugs of high potency generally have a high affinity for the receptors and thus occupy a
significant proportion of the receptors even at low concentrations.
▪ Agonists also possess significant efficacy, whereas antagonists, in the simplest case,
have zero efficacy.
▪ Drugs with intermediate levels of efficacy, such that even when 100% of the receptors
are occupied the tissue response is submaximal, are known as partial agonists , to
distinguish them from full agonists , the efficacy of which is sufficient that they can elicit
a maximal tissue response
,THE BINDING OF DRUGS TO RECEPTORS
▪ The binding of drugs to receptors can often be measured directly by the use of drug
molecules (agonists or antagonists) labelled with one or more radioactive atoms
(usually 3 H, 14 C or 125 I).
▪ the radiolabelled drug will exhibit both specific binding (i.e. binding to receptors, which
is saturable as there are a finite number of receptors in the tissue) and a certain amount
of ‘non-specific binding’ (i.e. drug taken up by structures other than receptors, which, at
the concentrations used in such studies, is normally non-saturable), which obscures the
specific component and needs to be kept to a minimum ( Fig. 2.2A–B ).
▪ The amount of non-specific binding is estimated by measuring the radioactivity taken up
in the presence of a saturating concentration of a (non-radioactive) ligand that inhibits
completely the binding of the radioactive drug to the receptors, leaving behind the non-
specific component.
▪ This is then subtracted from the total binding to give an estimate of specific binding
( Fig. 2.2C ).
▪ The binding curve ( Fig. 2.2C–D ) defines the relationship between concentration and
the amount of drug bound (B),
▪ Measurement of receptor binding.
- (i) Cartoon depicting radioligand
(shown in red) binding to its
receptor (R) in the membrane as well
as to non-specific sites on other
proteins and lipid.
- (ii) when the concentration of
radioligand is increased all the specific
sites become saturated but non-
specific binding continues to increase.
- (iii) addition of a high concentration of a non-radioactive drug (shown in green) that
also binds to R displaces the radioactive drug from its receptors but not from the
non-specific sites. (B–D) Illustrate actual experimental results for radioligand binding
to β adrenoceptors in cardiac cell membranes
▪ (B) Measurements of total and non-specific binding at equilibrium.
- Non-specific binding is measured in the presence of a saturating concentration of a
non-radioactive β-adrenoceptor agonist, which prevents the radioactive ligand from
binding to β adrenoceptors.
- The difference between the two lines represents specific binding. (C) Specific binding
plotted against concentration. The curve is a rectangular hyperbola.
- (D) Specific binding as in (C) plotted against the concentration on a log scale. The
sigmoid curve is a logistic curve representing the logarithmic scaling of the
rectangular hyperbola plotted in panel (C) from which the binding
parameters K (the equilibrium dissociation constant) and B max (the binding
capacity) can be determined.
, ▪ Binding curves with agonists often reveal an apparent heterogeneity among receptors.
- agonist binding to muscarinic receptors and also to β adrenoceptors suggests at
least two populations of binding sites with different affinities.
- the receptors can exist either unattached or coupled within the membrane to
another macromolecule, the G protein, which constitutes part of the transduction
system through which the receptor exerts its regulatory effect.
- Antagonist binding does not show this complexity, probably because antagonists, by
their nature, do not lead to the secondary event of G protein coupling. Because
agonist binding results in activation, agonist affinity has proved to be a surprisingly
elusive concept, about which aficionados love to argue.
THE RELATION BETWEEN DRUG CONCETRATION AND EFFECT
▪ Although binding can be measured directly, it is usually a biological response, such as a
rise in blood pressure, contraction or relaxation of a strip of smooth muscle in an organ
bath, the activation of an enzyme, or a behavioural response, that we are interested in,
and this is often plotted as a concentration – effect curve (in vitro) or dose– response
curve (in vivo)
▪ This allows us to estimate the maximal response that the drug can produce ( E max ), and
the concentration or dose needed to produce a 50% maximal response (EC 50 or ED 50 )
SPARE RECEPTORS
▪ many full agonists were capable of eliciting maximal responses at very low occupancies,
often less than 1%.
- This means that the mechanism linking the response to receptor occupancy has a
substantial reserve capacity.
- Such systems may be said to possess spare receptors , or a receptor reserve.
▪ The existence of spare receptors does not imply any functional subdivision of the
receptor pool, but merely that the pool is larger than the number needed to evoke a full
response.
▪ This surplus of receptors over the number actually needed might seem a wasteful
biological arrangement.
▪ it is highly efficient in that a given number of agonist–receptor complexes,
corresponding to a given level of biological response, can be reached with a lower
concentration of hormone or neurotransmitter than would be the case if fewer
receptors were provided.
COMPETITVE ANTAGONISM
▪ In the presence of a competitive antagonist, the agonist occupancy (i.e. proportion of
receptors to which the agonist is bound) at a given agonist concentration is reduced,
because the receptor can accommodate only one molecule at a time.
- However, because the two are in competition, raising the agonist concentration can
restore the agonist occupancy (and hence the tissue response).
- The antagonism is therefore said to be surmountable
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