1. Receptors & Drug action at Receptors
Chapter 4
Lecture 8
Dr Brajesh Kumar

2. Introduction Target for drugs 1. Enzymes (major)
2. Receptors
Drugs which interact with receptors are amongst the
most important in medicine and provide treatment for
ailments such as pain, depression, Parkinson's disease,psychosis, heart failure, asthma, and many other
problems.

3. What is a Receptor?
The term “receptor” specifically refers to proteins that participate
in intracellular communication via chemical signals
A receptor is a protein molecule embedded within the cell membrane with part of its structure
facing the outside of the cell.
The beneficial therapeutic effects and unwanted toxic effects of drugs are
elicited through interactions with proteins
-Enzymes (aspirin + cyclooxygenase)
-Transporters/Carriers (Prozac + serotonin reuptake transporter)
-Ion Channels (local anesthetics + Na+ channels)
-Receptor Proteins (cimetidine + histamine receptor)
---Upon recognition of an appropriate chemical signaling molecule (ligand), receptor proteins
transmit the signal into a biochemical change in the target cell
----- Ligands include drugs as well as endogenous signaling molecules such as hormones and
neurotransmitters

4. The receptor role
Communication is essential for all the control in the body's
organs and functions.
Control and communication come primarily from the brain and spinal column (the central nervous system—CNS) which receives and sends messages via a vast network of nerves
Message as being an electrical 'pulse' which travels down the nerve
cell towards the target, The nerves do not connect directly to their
target cells. They stop just short of the cell surface 100 Aº,
Chemical messenger can diffuse across the gap between the nerve ending and the cell .
It can bind and interact with a receptor & result in a biological response/action.

5. The Lock and Key Model of Ligand- Receptor Interaction
-A ligand such as a hormone or neurotransmitter
(the "key") bind to specific receptors (the "lock”)
-this binding "unlocks" the cell's response.
-many drugs work by mimicking a naturally occurring hormone or neurotransmitter
-if the drug causes the receptor to respond in the same way as the naturally occurring substance, then the drug is
referred to as an agonist
-these are drugs that can “pick the lock”.
-other drugs work in the opposite way - as antagonists
-these drugs bind to the receptor, but do not produce a
response.
-because the drug prevents the receptor from binding
to the normal hormone or neurotransmitter, it has
an inhibitory effect on the naturally occurring substance.

6. Chemistry of Drug-Receptor Interactions
Most drug-receptor interactions
-reversible
-weak chemical bonds
Irreversible drug-receptor interactions
-not common
-strong chemical bonds (covalent)
-e.g. aspirin, anti-tumour drugs
-usually undesirable
-reversal of effects/toxicity
-mutagenicity/carcinogenicity
Hormones and neurotransmitters can be distinguished by the route they travel and by the way they are
released, but their action when they reach the target cell is the same. They both interact with a receptor and a message is received. The cell responds to that message, adjusts its internal chemistry accordingly and a biological response results.

7. Neurotransmitters
It include compounds(messenger) such as Acetylcholine, noradrenaline,
dopamine,7-aminobutanoic acid (GABA), serotonin, 5-hydroxytryptophan,
and even glycine
A nerve releases only one type of neurotransmitter & receptor awaits it on the target cell will be specific for that messenger

8. Difference between enzymes & receptors ?
In receptor there will be an area which has the correct shape to
accept the incoming messenger. This area is known as the binding
site and is analogous to the active site of an enzyme
-Chemical messenger does not undergo a chemical reaction
It fits into the binding site of the receptor protein, passes on its
message and then leaves unchanged.

9. How does the message get received?
If no reaction takes place, what has happened? How
does the chemical messenger tell the receptor its
message and how is this message conveyed to the cell?
Message get received or conveyed is related with shape
The messenger binds to the receptor and induces it to change shape. This
change subsequently affects other components of the cell membrane and leads
to a biological effect.
There are two main components involved:
Ion channels
(2) Membrane-bound enzymes

10. Ion channels & Membrane-bound enzymes
Messenger
Receptor
Cell membrane
Enzyme
Active Sites
Ion channels
Cell Cytoplasm
Membrane-bound enzymes

11. The design of agonists Following requirements in turn
The drug must have the correct binding groups.
The drug must have these binding groups correctly positioned.
The drug must be the right size for the binding site.
Agonist (e.g. drug, hormone, neurotransmitter) binding induces a
conformational change in the receptor from the inactive to active state
Conformational change to active state can also occur spontaneously in
the absence of agonist (random kinetic fluctuations)
Agonist dramatically increases the probability of conformational change
and stabilizes the active state

12. The design of antagonists
Antagonists acting at the binding site
Antagonists acting outwith the binding site-
Allosteric antagonists & Antagonism by the 'umbrella’ effect
• Bind to receptors, but do not activate signal transduction mechanisms
• Biological effects derive from preventing agonist (drugs, endogenous) binding
and receptor activation
Competitive Antagonists
-bind to same site on receptor as agonists
-inhibition can be overcome by increasing agonist concentration (reversible)
-primarily affect agonist potency
-clinically useful
Non-Competitive Antagonists
-bind covalently to same site as agonist (irreversible) or to a site distinct from that
of agonist (irreversible or reversible)
-inhibition cannot be overcome by increasing agonist concentration
-primarily affect efficacy
-limited clinical use

13. The switch: Allosteric inhibition
Allosteric means “other site”
Active site E
Allosteric site
These enzymes have two receptor sites
One site fits the substrate like other enzymes
The other site fits an Antagonist or inhibitor molecule
Antagonists fits into
allosteric site

14. The allosteric site the enzyme “on-off” switch
Active site E
Allosteric site empty E
Conformational change
Substrate
fits into the active site
Antagonist
molecule is
present
Substrate
cannot fit into the active site
The Antagonist
molecule is
absent
Antagonist
fits into
allosteric site
Antagonist behaves just like Inhibitors

15. Desensitization
• Effect of a drug often diminishes when given continuously
or repeatedly
• desensitization, tachyphylaxis, refractoriness, resistance,
tolerance
• receptor-mediated and non-receptor-mediated
mechanisms
Receptor Mediated
- loss of receptor function
- reduction of receptor number
Non-Receptor Mediated
- reduction of receptor-coupled signaling components
- reduction of drug concentration
- physiological adaptation