PHYSICAL CHEMISTRY

OF DRUG RECEPTOR
INTERACTION
What is a Drug Receptor?
- a specialized target macromolecule that binds a
drug and mediates its pharmacological action.
These receptors may be enzymes, nucleic acids,
or specialized membrane-bound proteins. The
formation of the drug-receptor complex leads to
a biological response.
Concepts of Drug Receptor
1. Receptors largely determine the
quantitative relations between dose or
concentration of drug and
pharmacologic effects.
Concepts of Drug Receptor

2. Receptors are responsible for

selectivity of drug action.
Concepts of Drug Receptor

3. Receptors mediate the actions of

pharmacologic agonists and
antagonists.
MACROMOLECULAR
NATURE OF DRUG
RECEPTORS
RELATION BETWEEN DRUG CONCENTRATION & RESPONSE

• Concentration-Effect Curves & Receptor

Binding of Agonists
• Receptor-Effector Coupling & Spare
Receptors
• Competitive & Irreversible Antagonists
• Partial Agonists
Agonist vs. Antagonist
An agonist is a drug that binds to the
receptor, producing a similar response to the
intended chemical and receptor. Whereas an
antagonist is a drug that binds to the receptor
either on the primary site, or on another site,
which all together stops the receptor from
producing a response.
Concentration-Effect Curves & Receptor Binding of Agonists
Receptor-Effector Coupling & Spare Receptors

• When a receptor is occupied by an agonist, the

resulting conformational change is only the first of
many steps usually required to produce a
pharmacologic response. The transduction
process that links drug occupancy of receptors
and pharmacologic response is often termed
coupling.
Receptor-Effector Coupling & Spare Receptors
• The concept of “spare” receptors, regardless of the
precise biochemical mechanism involved, can help us
to think about these effects. Receptors are said to be
“spare” for a given pharmacologic response if it is
possible to elicit a maximal biologic response at a
concentration of agonist that does not result in
occupancy of the full complement of available
receptors.
Competitive & Irreversible Antagonists
Partial Agonists
Other Mechanisms of Drug Antagonism
• Chemical Antagonism - occurs when drugs combine in
solution to produce an inactive product, reducing the plasma
concentration of free drug.
• Physiologic Antagonism - describes the behavior of a
substance that produces effects counteracting those of
another substance (a result similar to that produced by an
antagonist blocking the action of an agonist at the same
receptor) using a mechanism that does not involve binding
to the same receptor.
 SIGNALING
MECHANISMS & DRUG
ACTION
• Why do some drugs produce effects that persist for minutes, hours,
or even days after the drug is no longer present?
• Why do responses to other drugs diminish rapidly with prolonged or
repeated administration?
• How do cellular mechanisms for amplifying external chemical signals
explain the phenomenon of spare receptors?
• Why do chemically similar drugs often exhibit
extraordinary selectivity in their actions?
• Do these mechanisms provide targets for developing new
drugs?
Intracellular Receptors for Lipid-Soluble Agents

Several biologic ligands are sufficiently lipid-

soluble to cross 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.
Ligand-Regulated Transmembrane Enzymes
Including Receptor Tyrosine Kinases

This class of receptor molecules mediates the first steps in signaling

by insulin, epidermal growth factor (EGF), platelet-derived growth factor
(PDGF), atrial natriuretic peptide (ANP), transforming growth factor-β (TGF-β),
and many other trophic hormones. These 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.
Cytokine Receptor

Cytokine receptors respond to a heterogeneous group 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 this
case, the protein tyrosine kinase activity is not intrinsic to the
receptor molecule.
Ligand- and Voltage-Gated Channels

Cytokine receptors respond to a heterogeneous group 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 this
case, the protein tyrosine kinase activity is not intrinsic to the
receptor molecule.
G Proteins

Receptors coupled to G proteins are often called “G

protein-coupled receptors” (GPCRs) , “seven-transmembrane” (7-
TM), or “serpentine” receptors. GPCRs make up the largest
receptor family and are so-named because the receptor
polypeptide chain “snakes” across the plasma membrane seven
times.
Receptor Regulation
G protein-mediated responses to drugs and hormonal
agonists often attenuate with time. After reaching an initial
high level, the response (eg, cellular cAMP accumulation, Na +
influx, contractility, etc) diminishes over seconds or minutes,
even in the continued presence of the agonist. This
“desensitization” is often rapidly reversible; a second
exposure to agonist, if provided a few minutes after
termination of the first exposure, results in a response similar
to the initial response.
WELL-ESTABLISHED
SECOND
MESSENGERS
A. Cyclic Adenosine Monophosphate
(cAMP)
Cyclic adenosine monophosphate
(cAMP) is an important second
messenger mediating
physiological functions,
including metabolism, gene
expression, cell growth and
differentiation.
B. Phosphoinositides and Calcium

Another well-studied second messenger

system involves hormonal stimulation of
phosphoinositide hydrolysis. Some of the
hormones, neurotransmitters, and growth
factors that trigger this pathway bind to
receptors linked to G proteins, whereas
others bind to receptor tyrosine kinases.
C. Cyclic Guanosine Monophosphate
(cGMP)
Unlike cAMP, the ubiquitous
and versatile carrier of diverse
messages, cGMP has
established signaling roles in
only a few cell types.
Phosphorylation: A Common Theme
Almost all second messenger signaling involves
reversible phosphorylation, which performs two principal
functions in signaling: amplification and flexible regulation. In
amplification, rather like GTP bound to a G protein, the
attachment of a phosphoryl group to a serine, threonine, or
tyrosine residue powerfully amplifies the initial regulatory
signal by recording a molecular memory that the pathway has
been activated; dephosphorylation erases the memory, taking
a longer time to do so than is required for dissociation of an
allosteric ligand. In flexible regulation, differing substrate
specificities of the multiple protein kinases regulated by
second messengers provide branch points in signaling
pathways that may be independently regulated.
Reference

Katzung, B., Masters, S., & Trevor, A., (2010). Basic

and Clinical Pharmacology, 12th edition, Mc Graw
Hill Medical Pub.
END.