Harliansyah, Ph.DDept. Biochemistry, Faculty of

MedicineYARSI UNIVERSITY

LIGAND - RECEPTORLIGAND - RECEPTOR

Topics on Drug ReceptorsTopics on Drug ReceptorsReceptors

DefinitionsClassification

Ligands (Drugs)DefinitionsClassification

Ligand-Receptor interactionInteraction and consequenceReceptor-mediated mechanism of action

Drug ReceptorsDrug Receptors

Receptor: DefinitionsSynonym: 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 SitesDrug Binding Sites (Receptors and Acceptors)

Binding SiteSpecific and Saturable

ReceptorBinding Site + Effect

AcceptorBinding Site + no Effect

Types of BindingTypes of Binding

Reversible ionic attraction, hydrogen bonds

Slowly reversible /irreversiblehigh affinity non-covalent binding, covalent binding

Specific receptors and Non-Specific receptors and Non-specific drug targetsspecific drug targets

Non-specific drug targetsNon-specific drug targets- Water- H ion, OH ion- Metal ions as relatively specific receptors

Specific Receptors Specific Receptors (drug receptors)- Enzymes- Membrane sterols- DNA

Differences between Differences between Specific Receptors and Non-Specific Receptors and Non-specific Drug Targetsspecific Drug Targets

Specific receptors Specific receptors are stereoselectivecan be selectively blocked by antagonist drugs

are occupied at nanomolar or micromolar concentrations

LigandsLigands (Receptor binding (Receptor binding molecules)molecules)Drugs or endogenous compounds binding

to receptors are described as Ligands.

Ligands are classified into 2 groupsAgonistAgonist: molecule that binds to receptor and

produces similar response to that of the endogenous ligandPartial agonist agonist that produce partial

effect

AntagonistAntagonist: molecule that binds to a receptor, but does not cause a responseCompetitive reversible or weak bindingNon-competitive non-reversible or strong

binding

LigandsLigands (Agonist and (Agonist and Antagonist)Antagonist)

Affinity and EfficacyAffinity and EfficacyAffinity: the attraction of the drug for the receptor.high affinity: low concentrations bind

low affinity: high concentrations bind

no affinity: does not bindEfficacy: the intrinsic activityMax. effect efficacy = 1Min. effect efficacy = 0

Agonist and AntagonistAgonist and Antagonist

Affinity Efficacy

Agonist yes highPartial agonist yes lowAntagonist

Competitive low-medium noNon-competitive high

no

Classifications of Drug Classifications of Drug ReceptorsReceptors

Drug classification can be based on several things

Classified byGeneral characteristicsLocationConsequence of interactionSecondary chemical messenger involved in the transduction pathway

Etc.

Classifications of Drug ReceptorsClassifications of Drug ReceptorsBased on General Based on General characteristicscharacteristics

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 Classifications of Drug ReceptorsReceptorsBased on LocationBased on Location

Example 1 Receptors of the nervous systemPost-synaptic receptorPre-synaptic receptor

Example 2 Receptors that are on the surface and inside the cellsCell-surface receptor

Ion-channel-linked receptors

G-protein-linked receptors

Enzyme-linked receptorsIntracellular receptor

Classifications of Drug Classifications of Drug ReceptorsReceptorsBased on Consequence of Based on Consequence of InteractionInteraction

Stimulation or InhibitionOf an enzymeOf an organ activity

Stimulate or Inhibit heart contractilityContraction or Relaxation of muscle

Classifications of Drug Classifications of Drug ReceptorsReceptorsBased on Secondary Based on Secondary MessengersMessengers

Secondary messengers of the signal transduction processes are in different kinds and can be used to classify the receptors connected to them.

Drug

Receptors Effector or Target

Cyclic AMPCyclic GMPPhosphoinositolArachidonic acidCalcium ion

Drug-Receptor InteractionDrug-Receptor Interaction

Structure specific Stereo-selective Lock and key

mechanism

Drug + Receptor

Drug-receptor complex

Response

Transduction pathways

Affinity

Potency

Efficacy

Receptor-mediated Mechanism Receptor-mediated Mechanism of Actionof Action

drugs beneficial effectcaused by the drugs ability to

interact with the receptor and changephysiologicalor biochemicalor pathological processes

Then termed mechanism of drug action

Intermediate MessengersIntermediate Messengers or Second MessengersSecond Messengers

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

Signal transduction

Drug Binding Site Effect

intermediate messengerse.g. cyclic AMP

Mechanism of actionMechanism of action Classical ReceptorsClassical ReceptorsDrug actions on Classical receptors

ขึ้��นกั�บชน are based on types of LigandsAgonist -> StimulationAntagonist -> Inhibition

Neurotransmitter noradrenaline (NA) receptor

actionHormones

angiotensin receptor actionLocal hormones

histamine receptor action

Mechanism of actionMechanism of action Uptake CarriersUptake Carriers

Uptake carriers or Transport proteins can have a role in regulation of drug action

Example: Norepinephrine (NE) action

NEUptake carrier

NE release from nerve

Receptors

Neurotransmission

Reuptake

Rapid inactivation

Decrease NE action

Drug

Uptake inactivation

More NE

Increase NE action

X

Mechanism of actionMechanism of action Ion ChannelsIon Channels

drug - ion channel

enhances /inhibits action

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

Mechanism of actionMechanism of action EnzymesEnzymes

drug-enzyme interaction

inhibition of enzyme activity

• Neostigmine inhibits acetyl cholinesterase

• increased acetyl choline

• Aspirin inhibits cyclooxygenase

• decreased prostaglandins

Inhibition of Enzyme Inhibition of Enzyme ActivityActivity NeostigmineNeostigmine

Mechanism of of action:anti-cholinesteraseInhibits activity of acetyl-cholinesterase

Effects: increase Acetylcholine (ACh) levels in the synapse.

Clinical use: treatment of myasthenia gravis

Myasthenia Gravis: autoimmune disease

Action of NeostigmineAction of Neostigmine

SkeletalSkeletal MuscleMuscle

Somatic Nervous Somatic Nervous System (voluntary)System (voluntary)

AChACh

AChEAChE

acetateacetate cholinecholine

Nicotinic AChreceptor

N

N

N

N

NNeostigmine

Inhibition of Enzyme ActivityInhibition of Enzyme Activity AspirinAspirin

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

pain and fever

Clinical use: treatment of pain and fever

Inflammation Inflammation and COXand COX

Infection

Arachidonic Acid (released from cell membrane)

Prostaglandins

Pain Fever

Cyclooxygenase (COX)Cyclooxygenase (COX)

Action of AspirinAction of Aspirin

Infection

Arachidonic Acid (released from cell membrane)

Prostaglandins

Pain Fever

CyclooxygenaseCyclooxygenase

Aspirin