DRUG

RECEPTOR
INTERACTIONS
Dr. Siddhartha Dutta
Mamc, New Delhi
 CONTENTS
 Introduction
 Targetsfor drug binding
 Types of receptors
 Determinants of drug activity
 Receptor theories
 Drug receptor interactions
 Desensitisation and
tachyphylaxis
 Conclusion
 HISTORY
 1878 – John Langley

 1905 - Receptive substance on surface of skeletal

muscle mediate drug action. Different in different
species

 Paul Ehrlich designated 'receptor‘ to be anchoring

group of the protoplasmic molecule for the
administered compound

 “Corpora non agunt nisi fiata”

 1948 - Ahlquist showed the differential action of adrenaline
& demonstrated its effects on two distinct receptor
populations & the theory of receptor-mediated drug
interactions gained acceptance

 1970s - Pharmacology entered a new phase following the

development of receptor-labelling techniques which made
it possible to extract and purify the receptor material.
TARGETS FOR DRUG BINDING
Drug is any substance or
product that is used for
diagnosis, prevention,
treatment/cure of a disease
or is intended to be used to
modify or explore
physiological systems or
pathological states for
the benefit of the
 Cellular macromolecule, or an assembly of
macromolecules, mainly protein in nature
present on the surface of the cell membrane
or inside the cell, concerned directly and
specifically in chemical signaling between and
within the cells
 TYPES OF RECEPTORS

 Ligand Gated Ion Channels

 G-Protein Coupled receptors

 Enzyme Linked receptors

 Nuclear receptors
 LIGAND GATED ION CHANNELS

 Ionotropic Receptors
 Typically receptors on which
fast neurotransmitters act
 Timescale: Milliseconds
 Localization: Membrane
 Effector: Ion Channel
 Coupling: Direct
 Gating mechanism: conformational change occurs in
extracellular part of the receptor
 Examples: Nicotinic Ach Receptor, GABA-A Receptor,
Glutamate Receptor, Glycine receptor, 5–HT3, AMPA &
kinate receptors
 VOLTAGE OPERATED CHANNELS

 These channels open when the cell membrane

is depolarised. They underlie the mechanism of
membrane excitability

 Activation induced by membrane depolarisation

is short lasting, even if the depolarisation is
maintained

 The most important channels in this group are

selective sodium, potassium or calcium
channels
 G – PROTEIN – COUPLED RECEPTORS
 Largest family
 Metabotropic or 7–Transmembrane/Heptahelical (α-
helices) receptors
 Extracellular N-terminal domain and intracellular C-
terminal domain
 3rd cytoplasmic loop couples to the G- Protein
 Timescale : Seconds
 Location : Membrane
 Effector : Channel or Enzyme
 Coupling : G- Protein
 Examples : adrenoceptors, Muscarinic Ach, histamine,
serotonin, opioid, cannabinoid, amine, peptide, prostanoid
TARGETS FOR G-PROTEINS

 Adenylate cyclase
PHOSPHOLIPASE C/IP3/DAG
 Ion Channels like K⁺ and Ca⁺⁺ channels are controlled by
direct interaction between the βγ-subunit of G0 and the
channel

 Phospholipase A2(formation of arachidonic acid and

eicosanoids)

 Rho A/Rho kinase, a system that controls the activity of

many signaling pathways controlling cell growth and
proliferation, smooth muscle contraction, etc.

 Mitogen-activated protein kinase (MAP kinase), activated

by cytokines and growth factors acting on kinase-linked
receptors and by GPCR ligands. Controls processes
involved in cell division, apoptosis and tissue
regeneration
 KINASE LINKED AND RELATED RECEPTORS
 Large, heterogenous group responding mainly
to protein mediators.
 Timescale : Hours

 Location : Membrane

 Effector : Protein Kinases

 Coupling : Direct

 Examples : Insulin, Growth Factors, Cytokine,

ANF receptors
 NUCLEAR RECEPTORS

Two main categories:

1) Present in the cytoplasm, form homodimers and
migrate to the nucleus. Their ligands are mainly
endocrine in nature (e.g. steroid hormones)
2) constitutively present in the nucleus and form
heterodimers with the retinoid X receptor. Their ligands
are usually lipids (e.g. fatty acids).
 A third subgroup transduce mainly endocrine signals but
function as heterodimers with retinoid X receptor (e.g.
thyroid hormone).
 ligand-receptor complexes initiate changes in gene transcription
by binding to hormone response elements in gene
promoters and recruiting co-activator or co-repressor factors
 DRUG RECEPTOR INTERACTIONS

 LIGAND: Any molecule which attaches selectively

to particular receptor

 AFFINITY: Capability of drug to bind to the

receptor and form receptor complex

 INTRINSIC ACTIVITY: Ability of the drug to

trigger the pharmacological response after forming
complex
 DETERMINANTS OF DRUG ACTIVITY

 Efficacy: The ‘strength’ of the agonist–receptor

complex in evoking a response of the tissue

 Potency: Amount of drug needed to produce an

effect.
RECEPTOR THEORIES
 OCCUPATION THEORY, CLARK’S (1926)
 Drugs act on independent binding sites and activate them,
resulting in a biological response that is proportional to the
amount of drug-receptor complex formed.
 D + R  DR  RESPONSE

 Intensity of pharmacological effect is directly proportional to

number of receptors occupied

 The response ceases when this complex dissociates

 Maximal response occurs when all the receptors are
occupied at equilibrium
 Limitations ??
THE INDUCED-FIT THEORY, DANIEL KOSHLAND (1958)

 States that the morphology of the binding site is not necessarily

complementary to the preferred conformation of the ligand

 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 macromolecule is then translated into the
biological effect, eliminating the rigid and obsolete “ key and
lock” concept

 Agonist induces conformational change – response

 Antagonist does not induce conformational change – no
response
 PATON’S RATE THEORY (1961)
 The response is proportional to the rate of drug-Receptor
complex formation
 Effect is produced by the drug molecules based on the
rates of association and dissociation of drugs to and from
the receptors
 Antagonists act much more slowly than agonists do and
hence the rate of dissociation is inversely proportional to
the potencies of antagonists while is directly proportional
to the agonists

 Type of effect is independent of number of receptors rather

rate of binding and release from the receptor.
THE TWO-STATE (MULTISTATE) RECEPTOR MODEL

 Developed on the basis of the kinetics of

competitive and allosteric inhibition

 It postulates that a receptor, regardless of the

presence or absence of a ligand, exists in two
distinct states: the R(active) and R* (inactive)
states

 R and R* are in equilibrium (equilibrium constant

L), which defines the basal activity of the receptor

 Occupied receptor can switch from its ‘resting’ (R)

state to an activated (R*) state, R* being favored
by binding of an agonist but not an antagonist
 Added drug encounters an equilibrium
mixture of R and R*

 If it has a higher affinity for R* than for R,

the drug will cause a shift of the equilibrium
towards R* (i.e. it will promote activation
and be classed as an agonist)
 If its preference for R* is very large, nearly all
the occupied receptors will adopt the R* conformation
and the drug will be a full agonist (positive efficacy)
 Shows only a modest degree of selectivity for R*, a smaller
proportion of occupied receptors will adopt the R*
conformation(partial agonist
 Shows no preference, the prevailing R:R* equilibrium will not be
disturbed and the drug will be a neutral antagonist(zero efficacy)
 Shows selectivity for R it will shift the equilibrium towards R and
be an inverse agonist (negative efficacy)
 AGONIST
 A drug that binds to physiological receptor and
mimic the regulatory effects of endogenous
substance.

 It has high affinity and high intrinsic activity

 TYPES OF AGONISM
 Summation :- Two drugs eliciting same response, but
with different mechanism and their combined effect
is equal to their summation.

Aspirin Codiene

PG Opiods receptor

Analgesic+ Analgesic+

++
 Additive: combined effect of two drugs acting by same
mechanism
Aspirin NSAIDS

PG PG

Analgesic+ Analgesic+

++
 SYNERGISM (SUPRA ADDITIVE):-

The combined effect of two drug effect is higher than

either individual effect.

 1.Sulfamethaxazole+ Trimethoprim
 2. Levodopa + Carbidopa.
 PARTIAL AGONIST
 Full affinity + low intrinsic activity

 Partly as effective as agonist

 Greater affinity for RA than RI

 Cannot produce a full biological

response at any concentration

ex: Pentazocine
 INVERSE AGONIST:
 Full affinity & intrinsic activity<0(0 to-1)

 Inverse agonists bind with the constitutively active

receptors, stabilize them, and thus reduce the activity
(negative intrinsic activity).

 Eg. Beta carbolines on BZD receptor

 Chlorpheneramine on H1,
 Risperidone/clozapine/chlorpromazine on 5-HT2a
 Ziprasidone/olanzapine on 5-HT2c
 ANTAGONIST
 A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the
receptor. An antagonist has no activity.
Types of Antagonism
1. Chemical antagonism

2. Physiological /Functional antagonism

3. Pharmacokinetic antagonism

4. Pharmacological antagonism

 Competitive ( Reversible/irreversible)

 Non competitive (Irreversible)

 PHARMACOKINETIC ANTAGONISM

 Antagonist effectively reduces the concentration of the

active drug at its site of action
 Either by increased metabolic degradation, decreased
absorption or increased excretion

 A- Calcium & tetracycline, Cholestyramine & warfarin/digoxin

 D- Phenylbutazone & warfarin
 M- ↑ Phenobarbital/rifampicin & warfarin, rifampicin & OCP
↓ ciprofloxacin/chloramphenicol/erythromycin &
theophylline
 E- ↓ Probencid/aspirin/sulfonamides/thiazides/indomethacin &
penicillin/zidovudine, NSAIDS & methotrexate/ furosemide
 PHARMACOLOGICAL ANTAGONISM

Competitive antagonism- Reversible

- Irreversible

1) Reversible antagonism
 Antagonists that bind reversibly to the same receptor site as
that of an agonist

 Surmountable

 Shift of the agonist log concentration–effect curve to the right,

without change of slope or maximum effect

 Linear relationship between agonist dose ratio and antagonist

concentration
 Shift is expressed as a
dose ratio, r,
(the ratio by which the agonist
concentration has to be
increased in the presence of
the antagonist in order to restore
a given level of response)

 Agonist reduces the rate of association of the antagonist

molecules
 Consequently, the rate of dissociation temporarily exceeds
that of association, and the overall antagonist occupancy
falls.
IRREVERSIBLE ANTAGONISM
 It occurs when the antagonist dissociates very slow or not
at all from the receptors results no change when the
agonist applied.
 Antagonist effect cannot be
overcome even after increasing
the concentration of agonist

 Occurs with drugs that possess

reactive groups that form
covalent bonds with the receptor

 Aspirin, omeprazole and MAO inhibitors

 SPARE RECEPTORS
 Receptors are said to be spare when, the maximal
response can be elicited by an agonist at a
concentration that does not result in 100% occupancy of
available receptors

 Agonist has to bind only a portion of receptors for full effect-

increase sensitivity of the system

 Many full agonists are capable of eliciting maximal responses

at very low occupancies, often less than 1%

 Spare receptors, or a receptor reserve denotes that the pool

is larger than the number needed to evoke a full response

 For a biological response economy of hormone or transmitter

secretion is thus achieved at the expense of providing more
receptors
 DESENSITISATION & TACHYPHYLAXIS
 TACHYPHYLAXIS
 The effect of a drug gradually diminishes
when it is given continuously or repeatedly,
which often develops in the course of minutes

 Tolerance- Gradual decrease in responsiveness to a drug,

taking days or weeks to develop.

 Refractoriness is used to indicate loss of therapeutic

efficacy
 Drug resistance is used to indicate loss of effectiveness
 MECHANISM OF DESENSITISATION

 Change in receptors- Ion channels

 Translocation of receptors- beta adrenoreceptor

 Exhaustion of mediators-amphetamines

 Increased metabolic degradation-

alcohol/nitrates

 Physiological adaptation-thiazide
 BIASED AGONISM
 Biased agonism, the ability of a receptor to differentially
activate downstream signaling pathways depending on
binding of a “biased” agonist compared to a “balanced” agonist

 The ability of some ligands to selectively activate some

signaling pathways while blocking others

 Peptides PACAP1-27 and PACAP1-38 activate PACAP (pituitary

cyclase-activating polypeptide type 1) receptors to elevate
cyclic AMP and increase production of IP3

 The receptor is not the minimal unit of control of agonism, it is

the agonist-receptor complex that controls the ultimate
signaling event
 Nature of the receptor-active state and the interaction of the
activated receptor with the multiple cytosolic signaling
 Molecular dynamics predicts that when proteins such as
receptors change conformation, different regions of the
receptor change independently (i.e., the protein does not
form uniform global conformation)

 Signaling protein s interact with different regions of the receptor

 Unique receptor conformations stabilized by agonists most
likely will result in differential (biased) activation of cell signaling
pathways

 Activation of a receptor that interacts with multiple signaling

components in a cell most likely will never produce equal
activation of all pathways

 Functionally selective agonists are defined as having a

signaling bias different from that of the natural agonist
CONCLUSION
THANK YOU