Drug Action at Receptors
I. What are receptors? How do they work?
II. Drug action at receptors
Part I: What are receptors? How do they work?
Communication between
Nerve
nerves and cells
Signal
Nerves in CNS send messages
Messenger to target cells
Receptor
Cells of one tissue send
messages to other cells
Nucleus Chemical messenger =
Cell
neurotransmitter or hormone
Neurotransmitters
Cover gap between nerve and cell
Structures vary
Ions
Lipids, purines, peptides
Monoamines, amino acids
OH
HO NH2 HO HO NH2
NH2
N
HO H HO
Noradrenaline Serotonin Dopamine
Hormones
Endocrine, paracrine, autocrine
Receptors
Nerve 1
Blood Nerve 2
supply
Hormone
Neurotransmitters
Binding and Nerve
Signal
Nerve
action of
messenger Receptor
Messenger
Response
Nucleus
Cell Cell
Resting State
Messenger Induced fit Messenger
Messenger
Cell
Membrane Receptor
Receptor Receptor
Cell
Cell Cell
message
Message
Signal transduction mechanisms
Gated ion channel
Ion channels
A hypothetical neurotransmitter and
receptor:
What binding groups exist on the neurotransmitter?
On the binding site?
Lock-gate
mechanism
Receptor enzyme
Receptor enzyme
Serpentine receptor
Membrane-bound enzyme activation via G-proteins
Kinase signal cascade
Adhesion receptor
Steroid receptor
Nuclear receptors
An anticancer agent:
Tamoxifen (Nolvadex) Aminoglutethimide
(Orimeten, Cytadren)
NH2
O
(CH3)2N
O N O
H
CH2CH3
Part II: Drugs and receptors
Receptors are a major target for drugs
Faulty communication between nerves and
cells can lead to disease/ailments
Drugs:
Agonists
Antagonists
Agonists
Receptor binding site
Design of agonist:
1. Correct binding groups
2. Correctly positioned
3. Correct size
NH2 Me
HO
NH2 NH
Me
OH Me
H NH2
H3C H
Enantiomers
Asymmetrical Synthesis
Pharmacophore
Antagonists
Other types of antagonists:
Allosteric antagonists
Antagonism by the umbrella effect
Partial agonists
1. Small conformational change
NH
H3N N
NH
NH2
H2N N N
H
2. Multiple binding, same receptor
3. Multiple receptors (see Table 5.1)
Equilibrium between active and inactive
receptor conformations
Identifying the pharmacophore
Oxamniquine is an important Third World drug
used in the treatment of schistosomiasis (bilharzia).
Consider the structures below of oxamniquine (A)
and two of the additional drugs tested in the design
of oxamniquine. Based on these structures, draw
the pharmacophore of oxamniquine.
H H
N
N
NEt 2
O HN
HN
N
H3C
S
O2 N
CH3
Cl
OH CH3
A
Designing drugs
The structure of epinephrine is shown below.
Based on this structure, predict the binding site of an
adrenergic receptor
Design an agonist for your receptor
Design an antagonist for your receptor
HO
NH
HO
OH
Question…
What happens when a drug binds to the
receptor and stays for a prolonged period of
time?
1. Desensitization
2. Sensitization
1. Desensitization
Phosphorylation
Endocytosis
Reduction of receptors
2. Sensitization
Prolonged deactivation
by antagonist leads to
deficiency of messages
sent to cell
Leads to tolerance and
dependence