Receptor and Signal Transduction

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Receptor and Signal Transduction Receptor
Concept Dept. Pharmacology, Tzu Chi Univ. T.H.
Chiu I. References for the lecture II.
Development of receptor theory III. Contribution
from physical and biological chemistry IV.
Occupational theory V. Subsequent modifications
of occupational theory
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I. References for the lecture 1. R.R. Ruffolo,
Jr. Important concepts of receptor theory. J.
Auton. Pharmacol. 2277-295, 1982. 2. Chapter
15, Cell Communication, pp. 481-512.
From Essential Cell Biology, B. Alberts et
al., 1998 It provides a general schemes of
signal transduction. A good reading materials
for the beginners. 3. Signal Transduction,
C-H. Heldin M. Purton,eds. Chapman
Hall, 1996. A concise description of major
signal transduction pathways you always want but
afraid to ask. 4. See the handouts for the
other references relating to the receptor
concept.
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II. Development of receptor theory A.
Receptive substance Langley, 1878, studied the
mutual antagonistic effects of pilocarpine and
atropine on salivary secretion 1905, studied
the antagonism between nicotine and curare on
muscle contraction, led to the idea that nicotine
and curare acted on the same receptive
substance. B. Receptor Ehrlich, 1913,
experiments with tissue stains, snake venom,
and bacterial toxins (side chain theory to
describe the interaction between antigen and
antibody, and the concept of specific cell
surface receptors as the basis for targeting
bioactive agents to the appropriate responsive
cells). Awarded Nobel Prize in Medicine in 1908
(immunochemistry).
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Experimental observations supporting specific
cell surface receptors 1. Many drug responses
are obtained at very low doses or
concentrations. 2. Responses can be blocked by
other drugs of specific chemical structures
(stereo-specificity). 3. The selectivity of
agonists and antagonists is extremely dependent
on chemical structures, and very small changes
in structures can have profound effects on
pharmacological activities.
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C. Occupancy theory Number of receptors
occupied determines the response Clark,
1926 quantitative mathematical treatment of drug
effect Ariens, 1954 introduced intrinsic
activity as the effect caused by unit
drug-receptor complex Stephenson, 1956
Introduced efficacy as the capacity of a drug to
initiate a response Furchgott, 1966
Introduced intrinsic efficacy as a quantal unit
for the capacity of a drug to initiate a
stimulus from one receptor Spare
receptors Nickerson, 1956

Stephenson, 1956
Furchgott, 1955 (awarded
Nobel Prize in Medicine, 1999, for the
research on NO)
Ariens, 1960
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D. Rate theory Paton, 1961 proposed that
the effect was proportional to the rate of
drug-receptor interaction, rather than to the
number of receptors occupied by the drug.
Challenging conceptually, but of limited
applicability based on our current
understanding or receptor systems. E. Molecular
models Macromolecular perturbation theory,
Belleau, 1964 Mobile receptor hypothesis,
Cuatrecasas, 1974, explaining the interaction
between ßadrenoceptor and adenylyl cyclase
Allosteric theory, Monod, Wyman Changeux, 1965
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III. Contributions from physical biological
chemistry Pharmacological concepts
Chemical concepts Receptive
substance
Langley
1878, 1905
Lock
key fit of ES
Fisher, 1894 Receptor Ehrlich, 1913
Enzyme kinetics
Henri, 1902
Michaelis-Menten, 1913
Briggs-Haldane, 1925
Lineweaver-Burke, 1934 Occupancy theory Clark,
1926
Intrinsic activity Ariens, 1954

Efficacy Stephenson, 1956
Spare
receptors Nickerson et al., 1956
Intrinsic efficacy,
Furchgott, 1966
Induced-fit theory
Koshland, 1958
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Pharmacological concepts
Chemical concepts Rate theory Paton, 1961
Macromolecular perturbation theory

Belleau, 1964

Allosteric transition model
Monod, Wyman
Changeux, 1965 Ligand-induced
cooperative model
Koshland, Nemethy Filmer,
1966 Mobile receptor hypothesis

Cuatrecasas, 1974
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IV. Occupancy theory Quantitative
treatment by Clark
Interaction between drugs and receptors follows
Law of Mass Action.
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General assumption 1. One drug molecule
reversibly binds to one receptor molecule. 2. A
response results from steady-state occupation of
receptors. 3. A graded response is
obtained. 4. Response is proportional to the
number of receptors occupied. 5. EM is
proportional to RT occupied. 6. D gtgt RT 7.
The occupation of one receptor does not alter the
property of other receptors.
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V. Modifications of occupancy theory A.
Ariens treatment Effect is dictated by 2
independent parameters. 1. Affinity the ability
of a drug to bind
2. Intrinsic activity the ability of drugs to
induce an effect after binding

agonists possess both affinity and intrinsic
activity (1) antagonists possess affinity
but not intrinsic
activity (0)
partial agonists (or partial
antagonists) with intrinsic
activity between 0 and 1.
3. In some cases only a small percentage
of receptors needs to be occupied to elicit
a maximal response.
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Assumptions for full agonists are the same as in
the Clark treatment.
a effect per unit drug-receptor complex ED50
(from dose-response curve) as a measure of
affinity Maximal effect as a measure of
intrinsic activity
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B. Stephenson treatment Introduced a
parameter called stimulus, and the response is
some unknown function (f) of stimulus. Thus,
function f dissociates receptor stimulus and
tissue response as directly proportional
quantities. 1. Effect doe not need to be
linearly proportional to receptor
occupancy.
2. EM can be achieved with
occupation of small percentage of
receptors.
3. Different drugs may
induce same effects by occupying different
percentage of receptors.
4. It is possible for 2 full
agonists with intrinsic activity of 1 to have
different efficacies.
5. Consequence of spare
receptors on the relation between ED50 and
KD (KD gtgt ED50). ED50 concentration
required for a half-maximal response
KD concentration required to occupy 50
of receptors
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C. Furchgott treatment Introduced intrinsic
efficacy, e, which is the capacity of a drug
to initiate a stimulus from one receptor. Thus,
intrinsic efficacy was defined as a strictly
drug-related term, whereas Stephensons efficacy
was a drug- and tissue-related term.
2 tissue factors RT and f (the nature and
efficacy of the functions converting receptor
stimulus into tissue response) 2 drug factors
KD and e