LIGAND - RECEPTOR

Harliansyah, Ph.D Dept. Biochemistry, Faculty of Medicine YARSI UNIVERSITY

Topics on Drug Receptors

Receptors
Definitions Classification

Ligands (Drugs)
Definitions Classification

Ligand-Receptor interaction
Interaction and consequence Receptor-mediated mechanism of action

Drug Receptors
Receptor: Definitions
Synonym: Target molecule Macromolecule (or macromolecular complex)
which binds agonists with high structural selectivity with the consequence that a characteristic effect occurs

Or site of drug action responsible for the pharmacological effect The component of the organism with which the chemical agent was presumed

to interact.

Receptors can be any functional macromelecular component of the

organism

Drug Binding Sites

(Receptors and Acceptors)
Binding Site
Specific and Saturable

Receptor Binding Site + Effect

Acceptor Binding Site + no Effect

Types of Binding
Reversible

ionic attraction, hydrogen

bonds Slowly reversible /irreversible high affinity non-covalent binding, covalent binding

Specific receptors and Non-specific drug targets

Non-specific drug targets - Water - H ion, OH ion - Metal ions as relatively specific receptors Specific Receptors (drug receptors)

- Enzymes - Membrane sterols - DNA

Differences between
Specific Receptors and Non-specific Drug Targets
Specific receptors
are stereoselective can be selectively blocked by

antagonist drugs are occupied at nanomolar or micromolar concentrations

Ligands (Receptor binding molecules)

Drugs or endogenous compounds binding to receptors are described

as Ligands.

Ligands are classified into 2 groups Agonist: molecule that binds to receptor and produces similar response to
that of the endogenous ligand
Partial agonist agonist that produce partial effect

Antagonist: molecule that binds to a receptor, but does not cause a

response
Competitive Non-competitive

reversible or weak binding non-reversible or strong binding

Ligands (Agonist and Antagonist)

Affinity and Efficacy

Affinity: the attraction of the drug for

the receptor.
high affinity: low concentrations bind low affinity: high concentrations bind

no affinity:

does not bind

Efficacy: the intrinsic activity Max. effect efficacy = 1 Min. effect efficacy = 0

Agonist and Antagonist

Agonist Partial agonist

Affinity yes yes

low-medium high

Efficacy high low

no no

Antagonist Competitive Non-competitive

Classifications of Drug Receptors

Drug classification can be based on several things
Classified by General characteristics

Location
Consequence of interaction Secondary chemical messenger involved in the transduction

pathway Etc.

Classifications of Drug Receptors

Based on General characteristics

Based on general characteristics, drug receptors can be classified into 4 groups Classical Receptors Or Physiological receptors

Uptake carriers or Transport proteins Ion channels Enzymes

Classifications of Drug Receptors

Based on Location
Example 1 Receptors of the nervous system Post-synaptic receptor Pre-synaptic receptor
Example 2 Receptors that are on the surface and inside the cells Cell-surface receptor
Ion-channel-linked receptors G-protein-linked receptors Enzyme-linked receptors Intracellular receptor

Classifications of Drug Receptors

Based on Consequence of Interaction

Stimulation or Inhibition Of an enzyme Of an organ activity
Stimulate or Inhibit heart contractility Contraction or Relaxation of muscle

Classifications of Drug Receptors

Based on Secondary Messengers

Secondary messengers of the signal transduction processes are in

different kinds and can be used to classify the receptors connected to them.
Drug Cyclic AMP Cyclic GMP Phosphoinositol Arachidonic acid Calcium ion

Receptors

Effector or Target

Drug-Receptor Interaction

Structure specific

Drug + Receptor
Affinity

Stereo-selective
Lock and key mechanism

Drug-receptor complex
Transduction pathways

Response
Efficacy Potency

Receptor-mediated Mechanism of Action

drugs

beneficial effect caused by the drugs ability to interact with the receptor and change
physiological

or biochemical
or pathological processes

Then termed mechanism of drug action

Intermediate Messengers or Second Messengers

Activation of a receptor may initiate a series of events mediated by intermediate messengers.
Signal transduction

Drug

Binding Site
intermediate messengers e.g. cyclic AMP

Effect

Mechanism of action

Classical Receptors
Drug actions on Classical receptors are based on types of Ligands
Agonist

-> Stimulation Antagonist -> Inhibition

Neurotransmitter noradrenaline (NA)
Hormones angiotensin Local hormones histamine

receptor

action

receptor
receptor

action
action

Mechanism of action

Uptake Carriers
Uptake carriers or Transport proteins

can have a role in regulation of drug action Example: Norepinephrine (NE) action
Drug
Uptake inactivation
NE

Uptake carrier Reuptake

X
NE release from nerve

More NE
Receptors Increase NE action Neurotransmission

Rapid inactivation

Decrease NE action

Mechanism of action Ion Channels

drug - ion channel

enhances /inhibits action

e.g. Ca++ channel blocker (verapamil)

Mechanism of action

Enzymes
drug-enzyme interaction

inhibition of enzyme activity

Neostigmine inhibits acetyl cholinesterase

increased acetyl choline Aspirin inhibits cyclooxygenase decreased prostaglandins

Inhibition of Enzyme Activity Neostigmine

Mechanism of of action: anti-cholinesterase Inhibits activity of acetylcholinesterase Effects: increase Acetylcholine (ACh) levels in the synapse. Clinical use: treatment of myasthenia gravis

Myasthenia Gravis: autoimmune disease

Action of Neostigmine
Somatic Nervous System (voluntary)
N Nicotinic ACh

receptor

ACh

N
N

AChE

Skeletal Muscle
N

Neostigmine
acetate choline

Inhibition of Enzyme Activity Aspirin

Mechanism of action: cyclo-oxygenase inhibitor
Pharmacological effects: prostaglandin release pain and fever

Clinical use: treatment of pain and fever

Inflammation and COX

Infection

Arachidonic Acid
(released from cell membrane) Cyclooxygenase (COX)

Prostaglandins Pain Fever

Action of Aspirin
Infection

Arachidonic Acid (released from cell membrane)

Cyclooxygenase
Prostaglandins

Aspirin
Pain

Fever