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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