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Proff. & HOD
Dept. of Pharmacology
Drug Targets Sites
Drugs can interact with the following target sites in a cell
2. Ion channels which incorporate a receptor and act as
4. Carrier molecules
• Based on the drug target sites, the
mechanisms of drug action can be classified
– Receptor mediated mechanisms
– Non-receptor mediated mechanisms
• Receptor: It is a membrane bound or
intracellular macromolecular protein which is
capable of binding the specific functional
groups of the drug or endogenous substance.
• Binding of a drug with its receptor results in the
formation of drug receptor complex (DR) which
is responsible for triggering the biological
D+R= (DR) → Response
• Affinity: The capacity of a drug to form the complex
with its receptor (DR complex) e.g., the key entering
the hole of the lock has got an affinity to its levers.
• Intrinsic activity (or) Efficacy: The ability of a drug
to trigger the pharmacological response after making
the drug-receptor complex .
• Ligand: Any molecule which attaches selectively to
particular receptors or sites
• Agonists: Agent which activates a receptor to produce an effect similar to
that of the physiologic signal molecule
Have both high affinity as well as high intrinsic activity, therefore
can trigger the maximal biological response
• Antagonists: Agent which prevents the action of an agonist on a receptor
but doesn’t have any effect of its own.
Have only affinity but no intrinsic activity. These drugs bind to
the receptor and block the binding of an endogenous agonist.
• Partial agonists: Agent which activates a receptor to produce a sub
maximal effect but antagonizes the actions of full agonist.
Have full affinity but with low intrinsic activity and hence are only
partly as effective as agonists.
• Inverse (Negative) agonists: Agent which activates a receptor to produce
an effect in the opposite direction to that of the agonist
Have full affinity but intrinsic activity ranges between 0 to -1
• Four types of binding takes place between
the receptor and the drug molecule
1. Van der Waals forces
2. Hydrogen bonding
3. Ionic interaction
4. Covalent bonding
Types of Receptors and
Signal transduction mechanisms
Type I: Ionotropic receptors (Ligand gated ion channels)
Type II: Metabotropic receptors (G proteins coupled receptors(GPCR))
1. Adenyl cyclase: cAMP system
2. Phospholipase-C: Inositol Phosphate system
3. Ion channel regulation
Type III: Enzyme linked receptors
a. Intrinsic enzyme receptors
b. JAK-STAT-kinase binding receptors
Type IV: Receptors regulating gene expression
• Also called as “Ligand gated ion channels”
• These are cell surface receptors
• Enclose ion selective channels (for Na+
within their molecules.
• Agonist binding opens the channel, and causes
depolarization/hyperpolarization/changes in the ionic
• Examples: nicotinic cholinergic, GABA-A, glycine
(inhibitory), excitatory AA(kainate, NMDA or N-methyl
D-aspartate, quisqualate) and 5HT3 receptors
G-Protein coupled receptors
• These are a large family of cell membrane receptors linked to
the effector through GTP activated proteins (G-Proteins).
• G-Proteins: 7 helical membrane spanning hydrophobic amino
acid (AA) segments which run into 3 extracellular and 3
• Agonist binding site is located on extracellular face, while
another recognition site formed by cytosolic segments binds
the coupling G-protein.
• Examples: Muscarinic, Dopamine D2, β-adrenergic, α1-
adrenergic, α2-adrenergic, GABAB , 5-HT
• There are three major effector pathways through which GPCRs function
1. Adenyl cyclase: cAMP system: Activation of AC results in
intracellular accumulation of second messenger cAMP which functions
through cAMP dependant protein kinase (PKA). The PKA phosphorylates
and alters the functions of many enzymes, ion channels, transporters
and structural proteins.
2. Phospholipase-C: IP3-DAG pathway: Activation of Phospholipase-
C(PLc) hydrolises the membrane PIP2 to generate IP3 and DAG. IP3
and DAG enhances protein kinase C (PKc) activation by
3. Ion channel regulation: The activated G-proteins can also open or
close ionic channels specific for Ca2+
, without the intervention
of any second messenger like cAMP or IP3 and bring about
depolarization/hyperpolarization/changes in intracellular Ca2+
Enzyme linked receptors
• This class of receptors have a subunit with enzymatic property
(intrinsic) or bind a JAK (Janus-Kinase) enzyme on activation.
The agonist binding site and the catalytic site lie respectively on
the outer and inner face of the plasma membrane.
• Intrinsic enzyme receptors: The intracellular domain is either
a protein kinase or guanyl cyclase
Examples: Insulin, Epidermal growth factor (EGF), Nerve
growth factor (NGF) receptors
• JAK-STAT-kinase binding receptors: These do not have
intrinsic activity, but agonist induced dimerization increases
affinity for a cytoplasmic tyrosine protein kinase JAK.
Examples: Growth hormone, many cytokines, interferons
Receptors regulating gene
• These are intracellular (cytoplasmic or nuclear)
soluble proteins which respond to lipid soluble
chemical messengers that penetrate the cell
• Kept inhibited till the hormone binds
• Capable of binding to specific genes and facilitates
their expression so that specific mRNA is
• Examples: All steroid hormones, thyroxin, vit. D and
• By counterfeit or False incorporation
Eg: Sulfa drugs and anti-neoplastic drugs
• By virtue of being Protoplasmic poisons
Eg: Germicides and antiseptics
• Through formation of antibodies
Eg: Vaccines, Antisera
• Through placebo action
• Targeting specific genetic changes