Review

TRENDS in Pharmacological Sciences

Vol.25 No.4 April 2004

Principles: Receptor theory in

pharmacology
Terry Kenakin
Assay Development Compound Profiling, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park,
NC 27709, USA

Pharmacological receptor theory is discussed with

special reference to advances made during the past 25
years. Thus, the operational model has supplanted analysis of drug receptor interaction in functional systems
whereas the extended ternary complex model is used
routinely to simulate quantitatively G-protein-coupled
receptor (GPCR) behavior. Six new behaviors for
GPCRs, centered on spontaneous production of receptor active states, ligand-selective receptor active states,
oligomerization with other proteins (receptor and nonreceptor) and allosteric mechanisms, have been characterized and each holds the potential for new drug
discovery for therapeutic benefit.
Pharmacological receptor models (the first being an
operational black box) preceded accurate knowledge of
receptors by many years. In these cartoon-like schemes,
drugs bound to receptors (defined as specific recognition
units) to yield quanta of excitation to cells. Even this
imprecise scheme enabled the construction of rudimentary
receptor theory because the receptor was defined as the
minimal unit needed to characterize the pharmacology of
drugs; the cell simply furnished the herald for the drug
receptor events. Under these circumstances, null methods
(using equal functional responses) allowed the cancellation of cellular effects for quantification of drug receptor
activity. Instead of being concerned with diverse responses
to an agonist such as isoproterenol, including cardiac
inotropy, lusitropy, chronotropy, vascular relaxation,
pancreatic, lacrimal and salivary gland secretion, bronchiole, uterine and urinary bladder muscle relaxation,
decreased stomach motility, skeletal muscle tremor and
melatonin synthesis, the problem could be reduced to the
interaction of isoproterenol with b-adrenoceptors.
For models to be useful, they must describe data and
predict effects. To do this, a mathematical formalism is
required. A.J. Clark [1,2] (see [3] for history preceding
Clark) was the first to apply the mathematical approaches
used in enzyme kinetics systematically to the effects of
chemicals on tissues.
The general aimhas been to determine the extent to
which the effects produced by drugs on cells can be
interpreted as processes following known laws of physical
chemistry. (Clark, 1937) [1]
Corresponding author: Terry Kenakin (Terry.P.Kenakin@gsk.com).

Clark is credited with being the originator of receptor

theory. It might not be appreciated today how important
his application of simple chemical laws to systems of
infinitely greater complexity was to receptor pharmacology [2]. It is interesting to note the scientific atmosphere
in which Clark published these ideas. The prevailing
concepts in the years 1895 1930 were rooted in homeopathic theories (based on loose ideas around surface
tension of the cell membrane) such as the Arndt Schulz
law and the WeberFechner Law. Other vagaries, with little
physicochemical basis, such as the law of phasic variation,
essentially stating that certain phenomena occur frequently, were widely applied [4]. In this context the
influence of Clarks thinking (in the form of his two classic
books on receptor theory [1,2]) cannot be over-estimated.
Occupation theory
An important difference between the effects of drugs on
enzymes versus tissues is the quantification and prediction of agonist response. Empirical proportionality constants such as intrinsic activity [5] were used to make the
equations better describe the experimental data obtained
from tissues. Progress was made when a powerful framework was constructed around the theoretical quantities
stimulus, stimulus response functions and efficacy and
published in an article by R.P. Stephenson [6]. In general,
classical theory evolved chronologically through concepts
described by Clark and other researchers such as Ariens
[5,7], Colquhoun [8], Ehlert [9], Furchgott [10,11], Gaddum [12], MacKay [13], Paton [14], Rang [15], Schild
[16,17], Stephenson [5], Van Rossum [18] and Waud [19].
In terms of occupation theory, a response to ligand A is
described by the function:


A 1Rt 
Response f
Eqn 1
A KA
where 1 is intrinsic efficacy (inherent ability of the drug to
induce a physiological response), [Rt] is the receptor
density, f is a function that relates the initial strength of
activation (termed stimulus) to tissue response, and KA is
the equilibrium dissociation constant of the drug receptor
complex. With this model, drugs can be characterized with
system-independent parameters (affinity and relative
efficacy) in test systems and the effects applied to
therapeutically relevant systems.
New concepts arrived during the next 25 years to bring
receptor theory to its present state. These involved the

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187

isolation and biochemical study of receptors, application of

allosteric theories, use of recombinant receptor systems and
presentation of the operational model of receptor function.

drugs [21]. This model has gained widespread acceptance in

the pharmacological community and is the model of choice for
describing functional receptor pharmacology.

The operational model

One theoretical shortcoming of occupation theory is the ad
hoc nature of the efficacy term. In 1989, Black and Leff [20]
introduced a revolutionary idea that obviated the need for
an empirical constant to account for efficacy; this formed
the basis for the operational model. The ingenious premise
on which this model is built is the fact that the efficacy
term emerges from an experimentally observed behavior
of pharmacological systems, namely the saturable
relationship between receptor stimulation and the
observed response. The equation describing drug action
through the operational model is given as:

The biochemical study of GPCRs and the ternary

complex model
With the advent of biochemical binding techniques came the
capability of characterizing some of the players on the
pharmacological receptor stage. Benefiting most from
this increased technology was the study of G-protein coupled
receptors (GPCRs). The current model(s) of GPCR function
uses the concept of allosterism, which was first described for
ion channels [22,23] and enzymes [24] and subsequently
applied to receptors [7,25,26]. These ideas culminated in the
ternary complex model for GPCRs, which was first published
by De Lean and colleagues [27]. This model describes a
receptor that, when activated by an agonist, moves laterally
in the cell membrane to physically couple to a trimeric G
protein. This introduced a novel concept in receptor models,
namely a synoptic (affording a general view of a whole)
nature in which the sensitivity of the system (and potency of
agonists) was subject to the availability of an external
protein (i.e. a G protein). Supporting this model were data
showing that physical complexes between receptors and G
proteins could be isolated after addition of agonist to receptor
systems [28,29].

Response

A t Emax
At 1 KA

Eqn 2

(see Box 1 for definitions of terms). Changes in the value of t

lead to changes in the responsiveness of the system to
agonists; that is, t controls both the potency of the agonist
and the maximal response of the agonist (a reflection of
agonist efficacy). The tissue-specific component of t is
the concentration of agonist-bound receptor that produces
half the maximal tissue response. Thus, in highly coupled
tissues, this value will be small (i.e. a small amount of receptor
complex will produce a large response). However, the nature
of the agonist also matters because the more efficacious the
agonist, the smaller the amount of receptoragonist complex
that is required to produce a response. Therefore, agonists will
have a unique value of t for a given tissue. This allows
comparisons between agonists; that is, the relationship
between t values in one tissue will carry over to their
relationship in other tissues. Figure 1 shows the relative
agonist response to two agonists with a fixed ratio of efficacy.
With the operational model the relative agonist responses of
both agonists can be predicted in any receptor system if the
sensitivity of the system to one of the agonists is known. The
operational model can negate the effects of volume control
whereby differences in receptor density and efficiency of
receptor coupling cause differences in organ sensitivities to

Opening Pandoras (molecular) toolbox and extending

models
Before the widespread use of recombinant receptor
systems, pharmacologists were confined in terms of the
systems they had at their disposal. Most receptor work was
performed on relatively few isolated tissues (e.g. guineapig ileum, rat atria and rat trachea). As put succinctly by
Sir William Paton:
The guinea pig longitudinal muscle is a great gift to the
pharmacologist. It has low spontaneous activity; nicely
graded responses (not too many tight junctions); is highly
sensitive to a very wide range of stimulants; is tough, if
properly handled, and capable of hours of reproducible
behavior. (W.D.M. Paton, 1986) [30].

Box 1. The operational model of drug action

A basic premise of the operational model is the experimentally
observed fact that the relationship between receptor occupancy and
response very often is hyperbolic in nature. Thus, the ligand-occupied
receptor (AR) activates the cellular stimulus response cascade with a
general equilibrium dissociation constant denoted by KE (the concentration of the AR complex that produces 50% of the maximal response).

where [Rt] is the receptor density and KA is the equilibrium dissociation

constant of the agonist receptor complex. The constant used
to characterize the propensity of a given system and a given
agonist to yield a response is the ratio Rt =KE ; this ratio is denoted by
t. Substituting for t yields the working equation for the operational
model:

Response
AR

Emax
AR KE

Response

Eqn I

where Emax is the maximal response that can be obtained from

the system. The more efficient the process is from the production of
AR to response, the smaller is the value of KE : Substituting mass action
for the production of AR yields the equation for the operational model:
Response

A Rt  Emax
ARt  KE KA KE

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Eqn II

A t Emax
At 1 KA

Eqn III

To fit experimental data that produce a dose response curve with Hill
coefficients that are different from unity (i.e. as for a complex cellular
stimulusresponse coupling mechanism showing cooperativity) the
following equation is used:
Response

tn An Emax
A KA n tn An

Eqn IV

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Vol.25 No.4 April 2004

1.2
Fraction of maximal response

(a)

1.0
0.8

= 300
100

0.6

30
10

0.4

3
1

0.2

0.3
0.1

0.0
4

Log [agonist]

Fraction of maximal response

(b)

1.2

1 / 2 = 10
1.2

1 = 0.3

1.2

1 = 1

1.2

1 = 10

1.2

1 = 30

1.0

1.0

1.0

1.0

1.0

0.8

0.8

0.8

0.8

0.8

0.6

0.6

0.6

0.6

0.6

0.4

0.4

0.4

0.4

0.4

0.2

0.2

0.2

0.2

0.2

0.0
4 3 2 1

0.0
4 3 2 1

0.0
4 3 2 1

0.0
4 3 2 1

1 = 300

0.0
4 3 2 1

Log ([A] /KA)

TRENDS in Pharmacological Sciences

Figure 1. Doseresponse curves calculated using the operational model. (a) The response is calculated according to Eqn 2 in the main text, with varying values for t
(see Box 1 for the definition of t). It can be seen that the magnitude of t controls both the potency and the observed maximal response to the agonist. (b) The operational
model preserves activity relationships between agonists (A) across all physiological systems. The curves show responses to two agonists differing in intrinsic efficacy by a
factor of ten. The panel furthest to the left shows responses in the least efficiently receptor-coupled tissue. The value of t for the most efficacious agonist (t1, solid line) is 3
whereas the value for t of the less efficacious agonist is 0.3 (t2, dashed line). Progression of panels from left to right represents tissues of increasing efficiency of receptor
coupling and/or receptor density. The tissue component of KE (general equilibrium dissociation constant) has been changed to affect differences in the receptor coupling
efficiency of the tissues (hence the sensitivity to the agonists). Abbreviation: KA ; equilibrium dissociation constant of the agonistreceptor complex.

This uniformity allowed quantitative experimentation

that could be cross-checked in many laboratories; the
resulting data laid the groundwork for modern receptor
theory. However, with it came a lack of scope in terms of
being able to study receptors at the extremes of their
behaviors. With advances in technology and molecular
biology, new observations could be made in old systems by
using new approaches such as receptor point mutation,
fusion proteins and stimulus-biased cell lines (enriched
with selective G proteins through co-transfection and
selective mating of GPCRs and G-protein subunits). These
techniques have been coupled with the plethora of new
technologies to observe receptor interaction with proteins.
A classic example of the impact of recombinant systems
is the finding of constitutive activity (elevated agonistindependent receptor activity) by Costa and Herz [31] and
the definition of inverse agonism (ligand-induced reversal
of constitutive activity). This drug activity was thought to
be an oddity at the time, but was later seen to be rare only
because the eyes to see it were not readily available to
the pharmacological community at large. The increasing
use of recombinant constitutively active receptor systems
soon revealed that, as predicted by theory, inverse agonism
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is a common phenomenon (i.e. 85% of competitive

antagonists are inverse agonists [32]). The observation of
constitutive GPCR activity revealed a receptor behavior
that could not be described by the original ternary complex
model. Thus, the now commonly used extended ternary
complex (ETC) model for GPCRs was devised by Sammama and colleagues [33] (Figure 2 and Box 2).
The ETC model uses an important concept from twostate theory: the production of species bias with selective
affinity. This suggests a mechanism for ligand efficacy: the
selective affinity for different receptor species. It also gives
efficacy a vector quality because it can be negative [a , 1,
where a is the differential affinity of the ligand for the
activated receptor (Ra)] and positive (a . 1). The ETC
model has been referred to as a two-state model, probably
because of the two unliganded receptor species: inactive
receptor (Ri) and Ra. This is an unfortunate misnomer
because the model actually describes infinite receptor
states when the receptor is ligand bound (the multiplier g
confers a different affinity of the receptor for G proteins
when the receptor is ligand bound). Thus, every value of g
defines a new ligand-bound receptor state. This is
important to note in view of experimental evidence that

Review

TRENDS in Pharmacological Sciences

(a) Extended ternary complex model

Box 2. Ternary complex models for GPCRs

G
L

Kg
ARa

ARaG

Ka

Ka

Ka

Kg
Ra

Ri

R aG
G

(b) Cubic ternary complex model

L

ARiG

ARaG

Kg

Kg
K
L

ARi

Ri

LG=KG 1 agA=KA
A=KA 1 aL1 gG=KG L1 G=KG 1

Eqn I

where KA and KG are equilibrium dissociation constants (reciprocals

of association constants). Figure I shows the effects of changing a on
the dose response curves of a system with existing constitutive
activity (note the elevated basal activity in the absence of ligand).
Formally identical effects are observed with changes in g values. The
cubic ternary complex model (Figure 2b in the main text) allows
interaction between the Ri and G proteins.

RaG
1.2

Kg

Ka

K
ARa
L

RiG

The extended ternary complex (ETC) model (Figure 2a in the main

text) describes a receptor that can exist in two states, active (Ra) and
inactive (Ri), named for their ability to activate G proteins (G). These
conformations coexist according to an allosteric constant unique for
the receptor type (denoted L Ra =Ri : Ligands have affinity for Ri
denoted by Ka (equilibrium association constant) and a differential
affinity for Ra of aKa. Similarly, Ra that is not bound to ligand has an
affinity for G proteins of Kg ; ligands can confer a different affinity of
the receptor for G protein denoted gKg.
The ETC model describes response production (elevated concentrations of Ra and ARa) as a fraction of the total receptor species
(denoted by r) as:

Kg
Ra
TRENDS in Pharmacological Sciences

Figure 2. Ternary complex models for G-protein-coupled receptors (GPCRs). (a)

Extended ternary complex model. Receptor states (Ri) and (Ra) coexist according to
the allosteric constant L. G protein (G) enters the system and binds to the activated
receptor state Ra to produce the physiological response. Ligand A binds to either
receptor state and also to Ra when it is bound to the G protein. The propensity of the
system to produce constitutive activity (spontaneous formation of the active state
RaG species) is defined by the allosteric constant L {L [Ra]/[Ri]}. The affinity of
ligands for the receptors is given by Ka whereas the efficacy is described by two
terms, a and g. The term a is the differential affinity of the ligand for Ra and the term
g is the differential affinity of the ligand-bound ARa for G proteins. (b) Cubic ternary
complex model. The inactive receptor species Ri and ARi are allowed to interact
with G proteins (but not signal) in this variant model. b refers to the differential
affinity of the receptor active state (over the inactive state) for the G protein.

ligands confer unique conformations to receptors that

differ from the constitutively active receptor state [34].
In thermodynamic terms, there must be a provision for
the inactive receptor to also interact with G proteins; this
is allowed in a more complete but more complex model for
GPCRs, named the cubic ternary complex (CTC) model
(Box 2) [35]. Recent evidence indicates that antagonists
form GTP-sensitive, non-signaling ternary complexes with
receptors (e.g. opioid peptide receptors [36] and histamine
H2 receptors [37]) and that unliganded wild-type receptors
(e.g. pheromone receptors Ste2p and Ste3p [38], and
cannabinoid CB1 receptors [39]) and receptors bound to
inverse agonists {SR141716A (see Chemical names) for
CB1 receptors [40], and tiodidine for H2 receptors [37]} can
sequester G proteins (in the form of antagonist-bound,
non-signaling ternary complexes) from other systems to

Fraction of maximal response

ARi

189

Vol.25 No.4 April 2004

1.0
= 30

0.8
0.6

10

1
0.3

0.4

0.1
0.03

0.2

0.01

0.0
5

1
Log ([A]/KA)

TRENDS in Pharmacological Sciences

Figure I. Response according to the extended ternary complex model for

G-protein-coupled receptors (GPCRs). Response (ordinate axis) given as the
concentration of the response-producing species [RaG] [ARaG] as a fraction
of the total receptor number according to Eqn I. Curves were calculated for
agonists of fixed value for g (g 5) and varying magnitudes for a in a system
with constitutive receptor activity L 0:01:

reduce constitutive activity. These data suggest that the

CTC model applies for some receptor systems.
In the worst-case scenario, recombinant systems can
simply show uncharacteristic behavior of receptors or
receptors under extreme conditions (i.e. the data take on a
Pandora aspect whereby the resulting information is
misleading and dissimulating). From this standpoint, such
data reflect what a receptor can do, and not necessarily what
it does under normal physiological circumstances. However,
pathological processes change synoptic receptor systems to
set-points that might not have been imagined in normal in
vitro pharmacological test systems. Therefore, such
extremes can be therapeutically relevant.

Chemical names
SR141716A: N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1Hpyrazole-3-carboxamide HCl
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Beyond linkage models

Linkage models such as the ETC and CTC models are
extremely useful for deriving methods to quantify drug

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(a) No ligand present

Vol.25 No.4 April 2004

(b) Add ligand

(c)

1.2
0.20

0.20
0.15

S1

S7

0.00

S4
S1

[R] [AR]

0.8
0.6
0.4
0.2
0.0
1

10

20
30
40
50
Micro-conformations

60

S4

0.05

0.00

S10

S7

0.05

0.10

S10

0.10

0.15

Frequency

1.0

0.25

TRENDS in Pharmacological Sciences

Figure 3. Probabilistic view of receptor conformations. This model assumes that a receptor, not bound by ligand, possesses a particular state distribution in conformational
space and that ligands and/or G proteins change the resting distribution of the receptor states (micro-conformations) following binding. (a) The frequency of occurrence of
100 random receptor micro-conformations depicted as the height of the individual histograms. (b) Frequency of those same conformations in the presence of a saturating
concentration of a ligand that stabilizes each conformation by a factor unique to the particular ligand and each conformation. (c) Gaussian distributions for the
ensemble of receptor conformations not bound by a ligand (labeled R) and bound by a ligand (labeled AR). Some conformations are enriched by ligand binding at the
expense of others.

effect. However, they are constrained in that they must

specifically pre-define the species present in thermodynamic space. If there are more species than are defined, then
the models fall short. A completely different approach is
taken by a probabilistic model of GPCR behavior [41,42].
This model assumes that a receptor, not bound by ligand,
possesses a particular state distribution in conformational
space and that ligands and/or G proteins change the
resting distribution of the receptor states following
binding (i.e. some conformational states are enriched
by the presence of the ligand and some are depleted)
(Figure 3).
The pharmacological activity of a ligand is defined by
the quantity and type of receptor conformations that the
ligand stabilizes in conformational space. For example,
ligands that shift the distribution of conformations
towards those that interact with and activate G proteins
are agonists. The probability model is much more versatile
than linkage theory models because it can predict
receptor behavior beyond a single dimensional response
(i.e. G-protein activation). GPCRs are known to have a
wide range of behaviors (beyond activation of G proteins),
such as the ability to form homodimers, heterodimers and
higher-order oligomers and the ability to internalize,
desensitize and interact with other membrane proteins
such receptor activity-modifying proteins (RAMPs) and
receptor component protein (RCP). The probability model
can describe ligand efficacies as the formation of different
ligand-stabilized ensembles of receptor conformations.
Thus, the coincidence of ligand-formed ensembles with
physiologically relevant conformations defines the pharmacological activity of the ligand [43].
A renaissance in receptor theory?
The past 25 years have amounted to a virtual revolution in
pharmacology with respect to receptor theory. In some
cases, experiments necessitated modification of a theory,
as in the discovery of constitutive activity by Costa and
Herz [30] and the resulting ETC model [32]. In other cases,
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theory preceded experiment as, for example, in the

prediction of protean agonism (positive agonism in nonconstitutive systems and inverse agonism in constitutive
systems as a result of a . 1 and g , 1 in the ETC model
[44]) and experimental verification thereafter (b2-adrenoceptors [45], a2-adrenoceptors [46] and bradykinin receptors [47]). Similarly, the observation of non-signaling
antagonist ternary complexes and sequestration of G
proteins by receptors suggest an experimental verification
for the CTC model in some systems.
GPCRs are now seen as interactive informationprocessing units beyond switches for G proteins; some
of these receptor behaviors might have therapeutic
application. Figure 4 shows six GPCR receptor behaviors
that have been discovered during the past few decades
and might lead to new therapeutic horizons. The
discovery of constitutive activity has led to the definition
of a new drug class (inverse agonists). It is not clear to
what extent inverse agonism is therapeutically relevant.
However, for some receptors that are known to be
exceptionally constitutively active, inverse agonists
might be the ligand of choice. For example, appetite
control through ghrelin receptor antagonism [48] or
histamine H3 receptor blockade [49] might require
inverse agonism. Also, in some tumors, receptor overexpression might make inverse agonists useful modulators of cancer growth [50].
There is considerable evidence that drugs can form
ligand-specific receptor active states and thus select
certain metabolic pathways (Figure 4) [34]. This can
yield more-selective agonists (i.e. biased agonists [51])
such as [Gly1,Arg19]hPTH1 28, a parathyroid hormone
(PTH) receptor agonist that activates cAMP but lacks the
activation of phospholipase C that is normally elicited
concomitantly by the natural hormone PTH [52]. This
concept extends beyond G-protein signaling, and is
demonstrated by, for example, the opioid receptor agonists
methadone and 1-a-acetyl methadone, which exhibit
reduced propensity to produce desensitization [53].

Review

(f) Receptor dimerization

TRENDS in Pharmacological Sciences

25-year receptor revolution

(a) Spontaneously occurring

active states
New mechanisms
of signaling

Ri (inactive)

Constitutive activity,
inverse agonism
Ra (active state 1)

(e) Allosterism

Drug-like
molecules for
peptide receptors

191

Vol.25 No.4 April 2004

(b) G-protein pleiotropy

G
Ra (active state 2)

(d) Auxiliary coupling

proteins
(i.e. RAMPs, RCP)

Organ-selective and
ligand-selective
agonists

(c) Agonist-selective
active states
G
Tissue-directed
recombinant screening
Phenotypic versus genotypic
organ selectivity
TRENDS in Pharmacological Sciences

Figure 4. Discoveries of G-protein-coupled receptor (GPCR) behavior through biochemical research conducted during the past 25 years. See the main text for specific details
and examples. Abbreviations: RAMPs, receptor activity-modifying proteins; RCP, receptor component protein.

Combinations of gene products (Figure 4) to yield drug

phenotypes in cells (phantom genes [21]) have led to
cell-specific drug sensitivity. For example, RAMPs [54] or
RCPs can completely change the agonist and antagonist
recognition properties of calcitonin and adrenomedullin
receptors. This severely undermines the historical notion
that the receptor is the minimal unit for drug recognition
and activity.
Increased functional screening of drugs is leading to a
concomitantly increased availability of allosteric drugs
(Figure 4) [55]. These ligands challenge conventional
classification (e.g. the muscarinic acetylcholine receptor
agonist effects of alcuronium are insensitive to the
muscarinic receptor antagonist quinuclidinyl benzoate
[56]). The advent of allosterism in receptor function will
allow the investigation of probe-specific effects that are not
possible with previous orthosteric analogs of natural
ligands. For example, although blockade of the chemokine
receptor CXCR4 is an important therapy for X4 HIV entry
[57], knockout studies suggest that blockade of chemotaxis
through this receptor can also lead to deleterious effects
[58]. However, there are allosteric ligands (i.e. peptide
L5H) that block HIV entry but do not affect CXCR4
function, which suggests a new approach to this problem
[59]. Finally, another type of phantom gene profile can be
observed with receptor dimerization (Figure 4), as in the
unique opioid receptor profile produced by the heterodimerization of kappa and delta opioid receptors [60].
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The next 25 years?

Considering the advancements made over the past 25
years, it is difficult to envisage GPCR-based therapeutics
in the year 2029. However, in view of the emergence
of GPCRs as complex information-processing units that
are capable of differential cryptography, it might be
supposed that new chemical scalpels will glean therapeutically useful behaviors. The advancements made
during the past 25 years reinforce the belief that
receptor theory is an indispensable tool in the drug
discovery process.
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2 Clark, A.J. (1933) The Mode Of Action Of Drugs On Cells, Edward
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3 Maehle, A-H. et al. (2002) The emergence of drug receptor theory. Nat.
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4 Holmstedt, B. and Liljestrand, G. (1981) Readings in Pharmacology,
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