RECEPTORS

A receptor is the component of a cell or organism that interacts with a drug or other
biological ligands thereby initiating the chain of events leading to the drug or
ligand’s observed effects. Receptors have become the central focus of investigating
drug effects and their mechanism of action (Pharmacodynamics). Many drugs’
receptors have been isolated and characterized in detail, thus opening the way for a
proper understanding of the molecular basis of drug action. Most receptors for
clinically relevant drugs and almost all receptors are proteins, and proteins are
complex organic compounds consisting of many amino acids linked together
through peptide bonds and cross-linked between chains by sulfhydryl bonds,
hydrogen bonds Vander Waals force. There is a greater diversity of chemical
composition in proteins than in any other group of biologically active compounds.
Receptors being proteins having/possessing this diverse chemical composition, can
undergo several chemical interactions with drugs and other biological molecules.

NATURE OF RECEPTORS
Receptors are regulatory proteins, which mediate the actions of endogenous
chemical signals such as neurotransmitters, autacoids, and hormones. This class of
receptors mediate the effect of many of the most useful therapeutic agents. Other
classes of proteins have been identified as drug receptor enzymes which may be
inhibited (or commonly activated) by binding to a drug. Examples include
dihydrofolate reductase, the receptor for anticancer drug Methotrexate; 3-hydroxy,
3-methyl glutaryl- Coenzyme A (HMG-CoA) reductase the receptor for statins, and
various proteins and lipid kinases.
Transport proteins can be useful drug targets. Examples include Na+/K+ ATPase,
the membrane receptor for cardioactive digitalis glycosides, norepinephrine and
serotonin transporter proteins that are membrane receptors for antidepressant
drugs; and dopamine transporters that are membrane receptors for cocaine and a
number of psycho-stimulants.
Structural proteins are also important drug targets such as rubulin, the receptor
for anti-inflammatory agent Colchicine.
TYPES OF RECEPTORS AND THEIR SIGNALING MECHANISM
1. Intracellular Receptors for Lipid-soluble Agents
Different biological ligands are lipid soluble, making them capable of crossing the
plasma membrane and act on intracellular receptors. One class of such ligands
includes steroids (corticosteroids, mineralocorticoids, sex steroids, Vitamin D) and
thyroid hormone, whose receptors stimulate the transcription of genes by binding
to specific DNA sequences near the gene whose expression is to be regulated. For
example, the binding of glucocorticoid hormone to its normal receptor protein
relieves an inhibitory constraint on the transcription-stimulating activity of the
protein. In the absence of the hormone, the receptor is bound to hsp90 (a heat
shock protein 90), which prevents the normal folding of several structural domains
of the receptor. The binding of hormones to the ligand-binding domain triggers the
release of hsp90. This allows the DNA-binding and transcription-activated
domains of the receptor to fold into their functionally active conformation so that
the activated receptor can initiate transcription of the target gene

2. Ligand Regulated Transmembrane Enzymes Receptors including

Tyrosine Kinases
This class of receptors mediates the first steps in the signaling of Insulin, epidermal
growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic
peptide (ANP), transforming growth factor-β (TGF- β), and many more other
trophic hormones. These types of receptors are polypeptides consisting of an
extracellular hormone binding domain and a cytoplasmic enzyme domain, which
may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase. In all of
these receptors, the two domains are connected by a hydrophobic segment of the
polypeptide that resides in the lipid bilayer of the plasma membrane. The receptor
tyrosine kinase signaling function begins with binding the ligand, a polypeptide
hormone or growth hormone, to the receptor’s extracellular domain. This brings
about a change in the receptor conformation causing two receptor molecules to
bind to one another (dimerize). The binding of the two receptor molecules activates
the tyrosine kinase enzyme activity present in the cytoplasmic domain of the dimer
leading to the phosphorylation of the receptors as well as additional downstream
signaling protein. Activated receptors catalyze phosphorylation of tyrosine residues
on different target signaling proteins, thereby allowing a single activated receptor
complex to modulate several biochemical processes.
Insulin, for instance, utilizes a single class of tyrosine kinase receptors to trigger
the increased uptake of glucose and amino acids and to regulate the metabolism of
glycogen and triglycerides in the cell. Activation of the receptors in specific target
cells drives a complex program of cellular events ranging from altered membrane
transport of ions and metabolites to changes in the expression of many genes.
Inhibitors of particular receptor tyrosine kinases are used in treating neoplastic
disorders (cancers) in which excessive growth factor signaling is often involved.
Some of these inhibitors are monoclonal antibodies e.g., transzumab (etuximab),
which binds to the extracellular domain of a particular receptor and interferes with
the binding of growth factor. Other inhibitors are membrane permanent small
molecule chemicals (e.g., gefitinib, erlotinib), which inhibit the receptor’s kinase
activity in the cytoplasm.

3. Cytokine receptors
Cytokine receptors respond to different groups of peptide ligands, which include
growth hormone, erythropoietin, several kinds of interferon, and other regulators of
growth and differentiation. These receptors use a mechanism closely resembling
that of receptor tyrosine kinases, except that in the case of cytokine receptors, the
protein tyrosine kinase activity is not intrinsic to the receptor molecule. Instead, a
separate protein tyrosine kinase from the Janus-Kinase (JAK) family, binds
noncovalently to the receptor. As in the case of the EGF receptor, cytokine
receptors dimerize after they bind the activating ligand, allowing the bound JAKs
to become activated and phosphorate tyrosine residues on the receptors.
Phosphorylated tyrosine residues on the receptor’s cytoplasmic surface then set in
motion a complex signaling dance by binding another set of proteins, called STATs
(Signal transducers and activators of transcription). The bound STATs are
themselves phosphorylated by the JAKs, the two STAT molecules dimerize
(attaching to one another’s tyrosine phosphates), and finally the STAT/STAT dimer
dissociates from the receptors and travels to the nucleus where it regulates
transcription of specific genes.

4. Ion Channels
Many of the most useful drugs in therapeutics act on ion channels. For ligand-
gated ion channels, drugs often mimic or block the actions of natural agonists.
Natural ligands of such receptors include acetylcholine, serotonin, GABA, and
glutamate, all of these are synaptic transmitters.
Each of their receptors transmits its signal across the plasma membrane by
increasing the transmembrane conductance of the relevant ion and thereby altering
the electrical potential across the membrane. For instance, acetylcholine causes the
opening of the ion channel in the nicotinic acetylcholine receptor (nAChR), which
allows Na+ to flow down its concentration gradient into cells, producing a
localized excitatory postsynaptic potential – a depolarization. The nacHR is one of
the best characterized of all cell-surface receptors for hormones or
neurotransmitters. One form of this receptor is a pentamer made up of four
different polypeptide subunits (for example 2 α-chains plus 1β, one ϒ, and one δ
chain). These polypeptides crossed the lipid bilayer 4 times to form a cylindrical
structure that is approximately 10nm in diameter but is impermeable to ions. When
acetylcholine binds to sites on the α-subunits, α conformational change occurs that
results in the transient opening of a central aqueous channel, approximately 0.5nm
in diameter, through which sodium ions penetrate from the extracellular fluid to
cause electrical depolarization of the cell.
The structural basis for activating other ligand-gated channels has been determined
in recent times and similar principles apply, however, there are differences in key
details that may open new opportunities for drug designs and action. For instance,
receptors that regulate excitatory neurotransmitters in the central nervous system
(CNS) synapses bind glutamate, a major excitatory neurotransmitter, through a
large appendage domain that protrudes from the receptor and has been called a
“flytrap” because it physically closes around the glutamate molecule, the glutamate
loaded flytrap domain then moves as a unit to control pore opening. Drugs can
regulate the activity of such glutamate receptors by binding to the flytrap domain,
to surfaces on the membrane-embedded portion around the pore, or within the pore
itself.

5. G Proteins & Second Messengers

Numerous extracellular ligands act by increasing the intracellular concentration of
second messengers such as cyclic adenosine 3, 5- monophosphate (cAMP),
calcium ions, or phosphoinositides. In most instances, they use a transmembrane
signaling system with three separate components. In the first instance, the
extracellular ligand is selectively detected by a cell surface receptor. The receptor
in turn triggers the activation of a GTP-binding protein (G-protein) located in the
cytoplasmic face of the plasma membrane.
The activated G protein then changes the activity of an effector element, usually an
enzyme or ion channel. This element then changes the concentration of the
intracellular second messenger. For cAMP, the effector enzyme is adenyl cyclase, a
membrane protein that converts intracellular adenosine triphosphate (ATP) to
cAMP. The corresponding G-protein Gs, stimulates adenyl cyclase after being
activated by hormones and neurotransmitters that act via specific Gs-coupled
receptors. There are many examples of such receptors, which include β-
adrenoreceptor, glucagon receptors, thyrotropin receptors, and certain subtypes of
dopamine and serotonin receptors. Gs and other G-proteins activate their
downstream effectors when bound by GTP and also have the ability to hydrolyze
GTP, this hydrolysis reaction inactivates the G protein but can occur at a relatively
slow rate, effectively amplifying the transduced signal by allowing the activated
(GTP-bound) G protein to have a longer lifetime in the cell than the activated
receptor itself. For example, a neurotransmitter such as norepinephrine may
encounter its membrane receptor for only a few milliseconds.
 Mechanisms of Drug Action
The effects of most drugs result from their interaction with macromolecular
components of the organism (receptors). Most drugs bind to those receptors to
bring about an effect. However, at the cellular level, drug binding is only the first
in a sequence of possible steps

a. Drug (D) + Receptor -effector (R) > Drug-receptor-effector-complex >

Effect
b. D+R > Drug-receptor complex > Effector molecule > Effect
c. D+R > D-R complex >activation of coupling molecule > Effector molecule
> Effect
d. Inhibition of metabolism of endogenous activator > Increased activator
action on an effector molecule > Increased effector
N.B 1: An effector or effector molecule is a molecule that binds to a specific
protein and regulates the latter or final stage of biological activity.
In other biological contexts, the term effector is used to describe an organ, a gland,
or a muscle that responds to nerve impulses. In addition, an effector can also be
described as a part of the body that can respond to stimuli according to the
instructions sent from the nervous system.
N.B. 2: Examples of effectors include muscles and glands, and so responses can
include muscle contractions or hormone release. In the G-protein coupled receptor
interaction, many proteins such as tubulins, adenylate cyclase, ion channels, and
others act as effectors since they are involved in the latter/nearer-to-the-end
biological activity.
N.B. 3: GTP means Guanosine triphosphate. GTP contains chemical energy stored
in its high-energy phosphate bonds. It releases energy which is broken down
(hydrolyzed) into GDP (Guanosine Diphosphate). The energy is used for many
metabolic processes such as gluconeogenesis and protein synthesis.
N.B. 4: Receptor-effector concept – the biological effect of chemical agents which
can only be the result of an interaction of the molecules of the active agents
(ligand/drugs) and particular molecule or molecular complexes present in the
biological organ/cell/system.
N.B. 5: Intrinsic Efficacy/Activity refers to the relative ability of a drug-receptor
complex to produce a maximum functional response
N.B. 6: Macromolecular Perturbation is an alteration of the function of a biological
system, induced by external or internal mechanism
Types of Drug-Receptor Interactions
1. Agonist Drugs: Agonist drugs bind to and activate the receptor in some
manner which directly or indirectly brings about the effect. Receptor
activation involves a change in conformation. Studies performed at the
molecular structure level show that some receptors incorporate effector
machinery in the same molecule so that drug binding brings about the effect
directly e.g., opening of ion channels or activation of enzyme activity. Other
receptors are linked through one or more intervening coupling molecules in
a separate effector molecule.
The receptor is postulated to exist partially in the inactive nonfunctional
form (Ri) and partially in the activated form (Ra). Agonists have a much
higher affinity for the Ra configuration and stabilize it so that a large
percentage of the total pool resides in the Ra-D fraction and a large effect is
produced. Many agonist drugs when administered at a concentration
sufficient to saturate the receptor pool can activate their receptor-effector
system to the maximum extent of which the system is capable, which means
they bring about a shift of almost all the receptor pool to the Ra-D pool.
Such drugs are termed FULL AGONIST. Other drugs, called PARTIAL
AGONISTS bind to the same receptors and activate them in the same way
but do not evoke as great response no matter how high the concentration,
that is to say that partial agonists do not stabilize the Ra configuration as full
agonists so that a significant fraction of the receptors exist in the Ri-D pool,
such drugs are said to have LOW INTRINSIC EFFICACY because they
occupy the same receptor sites, partial agonist can also prevent access by
full agonist. For example, pindolol, a β-adrenoceptor partial agonist, may
act either as an agonist (if no full agonist present) or as an antagonist (if full
agonist such as epinephrine is present).
 If a drug has a much stronger affinity for the Ri than the Ra state and
stabilizes a large fraction in the Ri-D pool, the drug will reduce any
constitutive activity thus resulting in effects that are the opposite of the
effects produced by conventional agonists at the receptor, such drugs are
termed INVERSE AGONISTS. Out of the best examples of such a system is
the ϒ-aminobutyric acid 1 (GABA1) receptor-effector (achloride channel)
in the nervous system. The receptor is activated by the endogenous
transmitter GABA and causes inhibition of post-synaptic cells. Conventional
exogenous agonists such as benzodiazepines also facilitate the receptor-
effector system and cause GABA-like inhibition with sedation as the
therapeutic effect. This sedation can be reversed by a conventional neutral
antagonist such as Flumazenil. Inverse agonists of this receptor system
cause anxiety and agitation, the inverse of sedation. Similar inverse agonists
have been found for β-adrenoceptors, Histamine H1 and H2 receptors, and
several other receptor systems.
Some drugs mimic (act like/copy/have a similar effect) agonist drugs by
inhibiting the molecules responsible for terminating the action of an
endogenous agonist. For example, Acetylcholinesterase inhibitors, slow the
destruction of endogenous acetylcholine causing a cholinomimetic effect
(an effect like that of the neurotransmitter Acetylcholine) that closely
resembles the action of cholinoceptor. Inhibitors do not bind to or only
incidentally bind to cholinoceptor (Ach receptors) because they amplify the
effect of the physiologically released endogenous agonist ligand, their
effects are sometimes more selective and less toxic than those of exogenous
agonists.

2. Antagonist Drugs: Antagonists are drugs that act by binding to a receptor,

compete with and prevent binding by another molecule. For instance,
acetylcholine receptor blockers such as Atropine are antagonists because
they prevent access of acetylcholine and similar agonist drugs to the
acetylcholine receptor site and they stabilize the receptors in their inactive
state (or some states other than the acetylcholine activated state). These
agents reduce the effects of acetylcholine and similar molecules in the body
but these actions can be overcome by increasing the dosage of agonists.
Some antagonists bind very tightly to the receptor site in an irreversible
manner and cannot be displaced by increasing the agonist concentration.
Drugs that bind to the same receptor but do not prevent the binding of the
agonists are said to act allosterically and may enhance or inhibit the agonist
molecule. Allosteric inhibition is not usually overcome by increasing the
dose of agonist.
Conventional antagonist action can be explained as fixing the fraction of
drug-bound Ri and Ra in the same relative amount as in the absence of any
drug. In this situation, no change in activity will be observed so the drug
will appear to be without effect. However, the presence of the antagonist at
the receptor site will block access of the agonist to the receptor and prevent
the usual agonist effect. Such blocking action can be termed neutral
antagonism.
 THEORIES OF DRUG ACTION
1. Occupation Theory
Drugs act on binding sites and activate them, resulting in a biological
response that is proportional to the amount of drug-receptor complex
formed. The response ceases when this complex dissociates.
The intensity of the pharmacological effect is directly proportional to
number of receptors occupied.
D + R ↔ DR → Response
The response is proportional to the fraction of occupied receptors. The
maximal response occurs when all the receptors are occupied

Limitation of the Occupation Theory

The occupation theory describes the relationship between dose and response
as a linear relationship, making the assumption that the maximal response of
the drug is equal to the maximal tissue response. This theory is most suited
to describe the behaviors of full agonists. Due to this limitation, Ariens
(1954) describes a situation where the maximal drug response is not equal to
the maximal tissue response (i.e., it permits the existence of partial agonist
drugs). This was done by using the modifier α, “intrinsic activity”. A full
agonist has an α-value of 1.0, if a drug only produces 50% of the maximal
tissue response it is a partial agonist with an α-value of 0.5.
Stephenson also postulated that drugs possess varying efficacies, such as
that a maximal response can be evoked by occupying differing fractions of
the receptor population.

2. Rate Theory
The response is proportional to the rate of drug-receptor complex formation.
Activation of receptors is proportional to the total number of encounters of a
drug with its receptors. According to this view, the duration of receptor
occupation determines whether a molecule is an agonist, or partial agonist
This theory is developed on the assumption that the excitation effect
(response) by a stimulant drug is proportional to the rate of drug-receptor
combination, rather than to the proportion of receptors occupied by the drug.
 The properties of a drug can then be specified by two rate constants K1- the
association rate constant and K2- the dissociation rate constant, the ratio
K2/K1 = Ke, corresponds to the reciprocal of the affinity. The value Ke then
determines potency and k2 determines whether the drug is a power
stimulant (K2 high), a partial agonist with the ability both to excite and to
antagonize (K2 moderate), or an antagonist with vestiges of stimulant action
(K2 low). Quantitatively such a theory accounts for the persistence of the
effect of an antagonist on a tissue, for the characteristic sequence of
excitation followed by block with drugs such as nicotine. The theory has
been tested on the guinea pig ileum with acetylcholine and histamine as
agonists; hyoscine, mepyramine, and atropine as antagonists; and
alkyetrimethylammonium compounds as partial agonists.

3. The Induced Fit Theory

According to this theory, binding produces a mutual plastic molding of both
the ligand and the receptor as a dynamic process. The conformational
change produced by the mutually induced fit in the receptor molecule is
then translated into the biological effect, eliminating the rigid and obsolete
“lock and key” concept of earlier times.
Agonists induce conformational change – response
Antagonist does not induce conformational change – no response
Partial agonists induce partial conformation change – partial response

4. Macromolecular Perturbation Theory

Suggests that when a drug-receptor interaction occurs, one of two general
types of macromolecular perturbation is possible: a specific conformational
perturbation leads to a biological response (Agonist), whereas a nonspecific
conformational perturbation leads to no biological response (Antagonist).

5. Activation Aggregation Theory

Receptor is always in a state of dynamic equilibrium between activated form
(Ra) and inactive form (Ri)
Ra ↔ Ri
Ra = Biological response
Ri = No biological response
 Agonists shift equilibrium to Ra
Antagonists shift equilibrium to Ri
Partial agonists bind to both Ra and Ri

TYPES OF BONDING (DRUG-RECEPTOR)

Drugs interact with receptors by means of chemical bonds. There are 3 major types
of bonds present:
A – Covalent
B – Electrostatic
C – Hydrophobic

A. Covalent Bonds: Covalent bonds are very strong and, in many cases, not
reversible, under biological conditions. Hence, the covalent bond formed
between the acetyl group of acetylsalicylic acid (Aspirin) and
Cyclooxygenase (its enzyme target in platelets) is not easily broken. The
platelet aggregation-blocking effect of aspirin lasts long after free
acetylsalicylic acid has disappeared from the bloodstream (about 15
minutes) and is reversed only by the synthesis of new enzymes in the
platelets, a process that takes several days. Other examples of highly reactive
covalent bond-forming drugs include DNA alkylating agents used in cancer
chemotherapy to disrupt cell division in the tumor

B. Electrostatic Bonding: Electrostatic bonding is much more common than

covalent bonding in drug-receptor interaction. Electrostatic bonds vary from
relatively strong linkages between permanently charged ionic molecules to
weaker hydrogen bonds and very weak induced dipole interactions such as
van der Waals forces and similar phenomena. Electrostatic bonds are weaker
than covalent bonds.

C. Hydrophobic Bonds: Hydrophobic bonds are usually quite weak and are
probably important in the interaction of highly lipid-soluble drugs with the
 lipids of the cell membrane and perhaps in the interaction of drugs with the
internal walls of receptor “pockets”

The specific nature of a particular drug-receptor bond is of less practical

importance than the fact that drugs that bind through weak bonds to their
receptors are generally more selective than drugs that bind using very strong
bonds. This is because weak bonds require a very precise fit of the drug to
its receptor if an interaction will occur. Only a few receptor types are likely
to provide such a precise fit for a particular drug structure. Thus, to design a
highly selective drug for a particular receptor, there is a need to avoid highly
reactive molecules that form weaker bonds. A few substances that are almost
completely inert in their chemical nature nevertheless have significant
pharmacological effects. For example, Xenon, an “inert gas”, has anesthetic
effects at elevated pressures.

Measurements of Drug Response: Graded, Quantal drug-response

curve
A. Graded Dose-Response Relations
This relationship helps us to choose among drugs and to determine
appropriate doses of a drug, the prescriber must know the pharmacologic
potency and maximal efficacy of the drug in relation to the desired
therapeutic effect. These two important terms can be explained by referring
to a graded dose-response curve which relates the dose of four different
drugs to the magnitude of a particular therapeutic effect.
1. Potency: Drugs A and B can be said to be more potent than drugs C and
D because of the relative positions of their dose-response curves along
the dose axis. Potency refers to the concentration (EC50) or (ED50) of a
drug required to produce 50% percent of that drug’s maximal effect thus
the pharmacological potency of drug A is less than that of drug B, a
partial agonist because of the EC50 of A is greater than the EC50 of B.
Potency of a drug depends in part of the affinity (Kd) of receptors for
binding the drug and in part on the efficiency with which the drug-
receptor interaction is coupled to response. Note that some doses of drug
A can produce larger effects than any dose of drug B, despite the fact that
we describe drug B as pharmacologically more potent. This is because
drug A has a larger maximal efficacy.
For therapeutic purposes, the potency of a drug should be stated in
dosage units, usually in terms of a particular therapeutic end point (e.g.
50mg for mild sedation, 1 mcg/kg/min for an increase in heart rate of 25
bpm). Relative potency, the ratio of effective doses (0.2 -10, etc) may be
used in comparing one drug with another.

2. Maximal Efficacy: This parameter reflects the limit of the dose-

response relation on the RESPONSE AXIS. Drugs A, C, and D have
equal maximal efficacy and all have greater maximal efficacy than drug
B. The maximal efficacy of a drug sometimes simply referred to as the
efficacy of a drug is very crucial for making clinical decisions when a
large response is needed. It may be determined by the drug’s mode of
interaction with receptors (as with the partial agonist) or by
characteristics of the receptor-effector system involved.
Thus diuretics that act on one portion of the nephron may produce much
greater excretion of fluid and electrolytes than diuretics that act
elsewhere. In addition, the practical efficacy of a drug for achieving a
therapeutic end point (e.g. increased cardiac contractility) may be limited
by the drug’s propensity to cause a toxic effect (e.g. fata cardiac
 arrhythmia) even if the drug could otherwise produce a greater
therapeutic effect.

B. Quantal Dose-Effect Curves

The graded dose-response curves have certain limitations in their application
to clinical decision-making. For instance, such curves may be impossible to
construct if the pharmacologic response is an either-or (quantal) event, such
as prevention of convulsions, arrhythmia, or death. Furthermore, the clinical
relevance of a quantitative dose-response relation in a single patient, no
matter how precisely defined, may be limited in application to other patients,
owing to the great potential variability among patients in the severity of
diseases and responsiveness to drugs.
Some of these difficulties may be avoided by determining the dose of drug
required to produce a specific magnitude of effect in a large number of
individual patients or experimental animals and plotting the cumulative
frequency distribution of responders versus the log dose. The specified
quantal effect may be chosen on the basis of clinical relevance (e.g. relief of
headache) or for the preservation of the safety of experimental subjects (e.g.
using low doses of cardiac stimulant and specifying an increase in heart rate
of 20 bpm as the quantal effect or it may be an inherently quantal event (e.g.
death of an experimental animal). For most drugs, the doses required to
produce a specified quantal effect in individuals are lognormally distributed,
that is a frequency distribution of such responses plotted against the log of
the dose, a Gaussian normal curve of variation.
When these responses are summated, the resulting cumulative frequency
distribution constitutes a quantal dose-effect curve of the percentage of
individuals who exhibit the effect plotted as a fraction of the log dose. The
quantal dose-effect curve is often characterized by stating the median
effective dose (ED50) which is the dose at which 50% of individuals exhibit
the specified quantal effect. Similarly, the dose required to produce a
particular toxic effect in 50% of animals is called the median toxic dose
(TD50). Thus if the ED50 of 2 drugs for producing a specified quantal
effects are 5 and 500mg respectively, then the first drug can be said to be
100 times more potent than the second for the particular effect.
 Quantal dose-effect curves may be used to generate information regarding
the margin of safety to be expected from a particular drug used to produce a
specified effect. One measure that reduces the dose of a drug required to
produce a desired effect to that which produces an undesired effect, is the
therapeutic index. In animal studies, the therapeutic index is usually defined
as the ratio of the TD50 to ED50 for some therapeutically relevant effect.

In conclusion, it is important to note that both curves provide information

regarding the potency and selectivity of drugs, the graded dose-response curve
indicates the maximal efficacy of the drug and the quantal dose-effect curve
indicates the potential variability of responsivesness among individuals.