DRUG-RECEPTOR INTERACTIONS
AND
PHARMACODYNAMICS
RAMLA KASHIF
OVERVIEW
Pharmacodynamics describes the actions of a drug on the body and the
influence of drug concentrations on the magnitude of the response.
Most drugs exert their effects, both beneficial and harmful, by
interacting with receptors present on the cell surface or within the cell.
The drug-receptor complex initiates alterations in biochemical and/or
molecular activity of a cell by a process called Signal Transduction.
SIGNAL TRANSDUCTION
Drugs act as signals, and their receptors act as signal
detectors.
Receptors transduce their recognition of a bound agonist
by initiating a series of reactions that ultimately result in a
specific intracellular response.
AGONIST
•Agonist refers to a naturally occurring small
molecule or a drug that binds to a site on a
receptor protein and activates it.
ANTAGONIST
•A receptor antagonist is a type of receptor ligand or
drug that blocks a biological response by binding to and
blocking a receptor rather than activating it like an
agonist. They are sometimes called blockers; examples
include alpha blockers, beta blockers, and calcium
channel blockers.
TARGETS FOR DRUG ACTION
The protein targets for drug action are
◦ Receptors
◦ Ion channels
◦ Enzymes
◦ Carrier molecules (transporters).
RECEPTORS
Receptor is a protein molecule found on the cell
surface (cell-surface or membrane receptor) or
within a cell, usually in its nucleus (nuclear
receptor) that recognizes and binds with specific
molecules, producing some effect in the cell.
LIGAND
A ligand is a substance that forms a complex with a
biomolecule to serve a biological purpose. In
protein-ligand binding, the ligand is usually a
molecule which produces a signal by binding to a
site on a target protein.
RECEPTOR
MAJOR RECEPTOR
FAMILIES
Ligand-gated ion channels
G protein- coupled receptors
Enzyme-linked receptors
Intracellular receptors (nuclear receptors)
LIGAND-GATED ION CHANNELS
Ligand-gated ion channels (LICs, LGIC), also commonly referred to
as ionotropic receptors, are a group of transmembrane ion-channel
proteins which open to allow ions such as Na +, K+ , Ca2 , and/or Cl−
to pass through the membrane in response to the binding of a
chemical messenger (i.e. a ligand), such as a neurotransmitter.
The extracellular portion of LGIC usually contains the ligand-
binding sites. This site regulates the shape of the pore through
which ions can flow across cell membrane.
When a presynaptic neuron is excited, it releases a
neurotransmitter from vesicles into the synaptic cleft.
The neurotransmitter then binds to receptors located on the
postsynaptic neuron.
If these receptors are ligand-gated ion channels, a resulting
conformational change opens the ion channels, which leads to a
flow of ions across the cell membrane.
This, in turn, results in either a depolarization, for an
excitatory receptor response, or a hyperpolarization, for
an inhibitory response.
Example: Stimulation of Nicotinic receptor by
acetylcholine results in sodium influx and potassium
outflux, generating an action potential in a neuron or
contraction in skeletal muscles.
G-PROTEIN COUPLED
RECEPTORS
G PROTEIN-COUPLED
RECEPTORS (GPCRs)
G protein-coupled receptors (GPCRs), also known as seven-(pass)-
transmembrane domain receptors, 7TM receptors, heptahelical
receptors, serpentine receptor, and G protein–linked receptors (GPLR)
GPCRs constitute a large protein family of receptors that detect molecules
outside the cell and activate internal signal transduction pathways and,
ultimately, cellular responses.
Coupling with G proteins, they are called seven-transmembrane
receptors because they pass through the cell membrane seven times.
The extracellular domain of this receptor contains the ligand-binding area
and the intracellular domain interacts (when activated) with a G protein or
effector molecule.
A diverse set of ligands bind to this type of receptor, including peptide
hormones, neurotransmitters, and odor molecules.
There are many kinds of G proteins for example, Gs, Gi and Gq, but they all
are composed of three protein subunits.
The alpha subunit binds guanosine triphosphate (GTP), and the beta and
gamma subunits anchor the G protein in the cell membrane.
Binding of an agonist to the receptor increases GTP binding to the alpha-
subunit, causing dissociation of the alpha-GTP complex.
These two complexes can then interact with other cellular effectors,
usually an enzyme, a protein or an ion channel, that are responsible for
further actions within the cell.
These reactions usually last several seconds to minutes.
Sometimes, the activated effectors produce second messengers that
further activate other effectors in the cell, causing a signal cascade effect.
WHAT ARE SECOND
MESSENGERS?
Second messengers or effector molecules are molecules
that relay signals received at receptors on the cell surface
— such as the arrival of protein hormones, growth factors,
etc. — to target molecules in the cytosol and/or nucleus.
Examples include cyclic AMP, cyclic GMP, inositol
trisphosphate, diacylglycerol, and calcium.
The second messengers relay the signals of hormones like
epinephrine, growth factors and others and cause some
kind of change in the activity of the cell.
Elevated concentration of second messengers leads to
rapid alteration in the activity of one or more cellular
enzymes.
Removal or degradation of second messenger terminate
the cellular response.
TYPES OF SECONDARY
MESSENGER
MOLECULES
There are three basic types of secondary messenger
molecules:
Hydrophobic molecules: water-insoluble molecules such as
diacylglycerol, and phosphatidylinositols, which are
membrane-associated and diffuse from the plasma
membrane into the intermembrane space where they can
reach and regulate membrane-associated effector proteins.
Hydrophilic molecules: water-soluble molecules, such as
cAMP, cGMP, IP3, and Ca2+, that are located within the
cytosol.
Gases: Nitric oxide (NO), carbon monoxide (CO) and
hydrogen sulfide (H2S) which can diffuse both through
cytosol and across cellular membranes.
ENZYME-LINKED
RECEPTORS
Enzyme-linked receptors are cell-surface receptors, where
the binding of an extracellular ligand causes enzymatic
activity on the intracellular side.
They have two important domains:
• Extra-cellular ligand binding domain
•Intracellular domain
The signaling molecule binds to the receptor outside of the
cell and causes a conformational change on the catalytic
function located on the receptor inside of the cell.
EXAMPLES OF
ENZYMATIC ACTION
Receptor tyrosine kinase, as an fibroblast growth factor
receptor. Most enzyme-linked receptors are of this type.
Guanylate cyclase, as in atrial natriuretic factor receptor.
4-NUCLEAR RECEPTOR
INTRACELLULAR RECEPTORS
(NUCLEAR RECEPTORS)
Intracellular receptors are receptors located inside the cell rather than on
its cell membrane, therefore ligand must diffuse into the cell to interact
with the receptor.
In order to move across the target cell membrane, the ligand must have
sufficient lipid solubility.
The primary targets of these ligand- receptor complexes are transcription
factors in the cell nucleus.
The activated ligand-receptor complex then translocates to the nucleus.
The activation or inactivation of these factors causes the
transcription of DNA into RNA and translation of RNA into
proteins.
Examples are the class of nuclear receptors located in the
cell nucleus and the IP3 receptor located on the endoplasmic
reticulum.
The ligands that bind to them are usually intracellular second
messengers like (IP3) and extracellular lipophilic hormones
like steroids hormones.
INTRACELLULAR
RECEPTORS:TYPES
Steroid hormone receptor:
•Sex hormones receptors (sex hormones)
Estrogen receptor
Androgen receptor
•Vitamin D receptor
•Glucocorticoid receptor
•Mineralocorticoid receptor
•Retinoic acid
ION CHANNELS
Ion channels are pore-forming membrane proteins which allow the
passage of ions in and out of a cell through the plasma membrane.
Ion channels can be classified by different properties, including by the
gating mechanism or the ion selectivity of the pore.
Ion channels are essential for life and play a fundamental role in
physiological processes such as muscle contraction and nutrient
transport.
CLASSIFICATION OF
ION CHANNELS
Classification by gating mechanism:
•Voltage-gated ion channels
•Ligand-gated ion channels (also known as ionotropic receptors)
•Light-gated ion channels
•Mechanosensitive ion channels
•Cyclic nucleotide-gated ion channels
•Calcium-gated ion channels
Classification by ion selectivity:
•Calcium
•Potassium
•Sodium
•Chloride
•Proton
•Non-selective (let any type of ion pass)
ION CHANNELS
Vasodilator drugs of the dihydropyridine
type which inhibit the opening of L-type
calcium channels.
Sulfonylureas used in treating diabetes,
which act on ATP-sensitive potassium
channels of pancreatic β-cells and thereby
enhance insulin secretion.
ENZYMES
An enzyme is a substance that acts as a catalyst in living
organisms, regulating the rate at which chemical reactions
proceed without itself being altered in the process.
The biological processes that occur within all living
organisms are chemical reactions, and most are regulated
by enzymes.
ENZYMES
Acetylcholinesterase inhibited by
neostigmine
Aspirin block COX enzyme
Levodopa (pro-drug) converted to
dopamine (drug)
TRANSPORTERS
Transporters (membrane transport/carrier proteins) are
specialized membrane-spanning proteins that assist in the
movement of ions, peptides, small molecules, lipids and
macromolecules across a biological membrane.
