DRUG-RECEPTOR INTERACTIONS
CHAPTER I: SIGNAL TRANSDUCTION
Asst. Prof. Dr. Emre Hamurtekin
EMU Faculty of Pharmacy
RECEPTOR FAMILIES
1. LIGAND-GATED ION
CHANNELS
2. G PROTEIN-COUPLED
RECEPTORS
3. ENZYME-LINKED
RECEPTORS
4. INTRACELLULAR
RECEPTORS
RECEPTOR FAMILIES
TRANSMEMBRANE LIGAND-GATED ION CHANNELS
 These are responsible for regulation of the flow of ions across
cell membranes.
 Response to these receptors is very rapid.
 Have role in;
 neurotransmission
 cardiac conduction
 muscle contraction etc...
 Cholinergic nicotinic receptors is an example to these type of
receptors.
G PROTEIN-COUPLED RECEPTORS
 They are made of a single α – helical peptide that has seven
membrane spanning regions.
G PROTEIN-COUPLED RECEPTORS
Second Messengers
 Essential in conducting and amplifying signals from G-protein
coupled receptors.
cAMP
cGMP
Ca
DAG
IP3
cAMP
cAMP
IP3 and DAG
ENZYME-LINKED RECEPTORS
 Spans the membrane once and may form dimers.
 These receptors also have cytosolic enzyme activity as an integral component of their
structure.
 Metabolism
 Growth
important functions controlled by these receptors.
 Differentiation
 Duration of responses to stimulation
minutes to hours
Most Common Enzyme-Linked Receptors
• EGF
• PDGF
tyrosine kinase activity
• ANP
• Insulin
INSULIN RECEPTOR
INTRACELLULAR RECEPTORS
 Receptor is entirely intracellular.
 Ligand must have sufficient lipid solubility.
 Ligands are mostly attached to plasma proteins in the blood




circulation.
Primary targets of these ligand-receptor complexes are
transcription factors.
DNA
RNA
proteins
Steroid hormones exert their effects by this receptor mechanism.
Time course of activation and duration of the response is much
longer than the other type of receptors.
DRUG-RECEPTOR INTERACTIONS
CHAPTER II: DOSE-RESPONSE RELATIONSHIPS
Asst. Prof. Dr. Emre Hamurtekin
EMU Faculty of Pharmacy
GRADED DOSE-RESPONSE RELATIONS
 As the concentration of a drug increases, the magnitude of its
pharmacological effect also increases.
GRADED DOSE-RESPONSE RELATIONS
 Two important properties of drugs can be determined by
graded-dose response curves;
 POTENCY
 EFFICACY
 POTENCY:
Measure of the amount of drug necessary to produce an effect
of a given magnitude.
Concentration of drug producing an effect that is 50% of the
maximum effect (EC50)
POTENCY
GRADED DOSE-RESPONSE RELATIONS
 EFFICACY:
Ability of a drug to elicit a response when it interacts with a
receptor.
Efficacy is dependent on;
 the number of drug-receptor complexes formed
 efficiency of the coupling of receptor activation to cellular responses.
Maximal efficacy of a drug assumes that all receptors are
occupied by the drug and if more drugs are added, no additive
response will be observed.
Maximal response (efficacy) is more important than drug
potency.
A drug with greater efficacy is more therapeutically beneficial
than the one that is more potent.
EFFICACY
DRUG CONCENTRATION and RECEPTOR BINDING
[DR]
[Rt]
=
[D]
Kd+[D]
 Kd can be used to determine the affinity of a drug for its




receptor.
Affinity: strength of interaction between a ligand and its
receptor.
High Kd: weak interaction-low affinity
Low Kd: strong interaction-high affinity
As the concentration of free drug increases, the ratio of the
concentrations of bound receptors to total receptors approaches
unity.
DRUG BINDING and PHARMACOLOGIC EFFECT
[E]
[Emax]
=
[D]
Kd+[D]
ASSUMPTIONS:
1. Binding exhibits no cooperativity.
2. Magnitude of the response is proportional to the amount of
bound receptors.
3. Emax occurs when all receptors are bound.
AGONISTS
 An agonist binds to a receptor and produces a biological
response.
Full agonists
2. Partial agonists
3. Inverse agonists
1.
 Full agonist:If a drug binds to a receptor and produces a
maximal biological response that mimics the response to the
endogenous ligand, it is known as a full agonist.
 Full agonist stabilizes the receptor in its
active state.
phenylephrine
α-1 adrenoceptors
Ca
BP
rises
PARTIAL AGONIST
 Partial agonist: Have efficacies greater then zero but less then
that of a full agonist.
 A partial agonist may have an affinity that is greater than, less
than or equivalent to that of a full agonist.
 Example: aripiprazole, an atypical neuroleptic agent.
INVERSE AGONIST
 They produce a response
below the baseline responses
measured in the absence of
drug.
 This decreases the number of
activated receptors to below
observed in the absence of
the drug.
 They exert the opposite
pharmacological effect of
receptor agonists.
INVERSE AGONIST
ANTAGONISTS
 Antagonists are drugs that decrease the actions of another
drug or an endogenous ligand.
 An antagonist has no effect if an agonist is not present.
 Antagonists produce no effect by themselves.
 Competetive antagonists
 Non-competetive (irreversible) antagonists
 Competetive antagonists: both the antagonist and agonist bind to the
same site on the receptor.
 Non-competetive antagonists: An irreversible antagonist causes a
downward shift of the maximum. And can not be overcome by
adding more agonist.
i.
ii.
Covalent binding to the active site of the receptor
Allosteric binding
ANTAGONISTS
FUNCTIONAL and CHEMICAL ANTAGONISM
 Functional (physiological) antagonism: An antagonist may act
at a completely separate receptor initiating effects that are
functionally opposite those of the agonist.
Example: Histamine vs. Epinephrine on bronchioles
 Chemical antagonism: Prevents the actions of an agonist by
modifying or sequestering the agonist, thus agonist can not
bind and activate its receptor.
Example: Heparine (acidic)vs. Protamine sulphate (basic)
THERAPEUTIC INDEX (TI)
 It is the ratio of the dose that produces toxicity to the dose
that produces effective response.
TI = TD50 / ED50
Therapeutic index is a measure of drug safety
Small therapeutic index: Warfarin
Large therapeutic index: Penicilin
THERAPEUTIC INDEX (TI)