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Molecular Targets For Drug Action (syllabus -prof.Kršiak)
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
Molecular Targets For Drug Action
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
RECEPTORS
Cell Membrane
Intracellular - Receptors linked to gene transcription (nuclear receptors)
Channel-linked receptors
G-protein-coupled receptors
Kinase-linked receptors
1. RECEPTORS
- about 90% of synapses in the CNS- for fast synaptic transmission (msec)- examples:
NICOTINIC, NMDA RECEPTOR: Na+ flows into cells, depolarization, excitation
GABAA RECEPTOR:Cl- flows into cells, hyperpolarization, inhibition
CHANNEL-LINKED RECEPTORS(„ionotropic receptors“)
CHANNEL-LINKED RECEPTORS(„ionotropic receptors“)
Katzung 2-12 ale raději GABAA
Katzung BG, 2001
Nicotinic receptor
pentameric structure - five subunits form a cluster surrounding a central transmembrane pore. When acetylcholine binds, the channel pore opens.
Remedia 1998
Cl-
Cl-- pentameric structure- receptor for GABA, for modulatory drugs (eg. benzodiazepines)
CHANNEL-LINKED RECEPTORS(„ionotropic receptors“)
GABAA receptor
Benzodiazep. receptor
- sites for action of about 45% of drugs- for slow synaptic transmission (seconds - minutes)-examples: beta-adrenergic receptors,
muscarinic receptors- „coupling“:
RECEPTOR - serpentine receptors: a polypeptide chain traverses the membrane seven times
G PROTEIN
EFFECTOR
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
Katzung Fig 2-14
Katzung BG, 2001serpentine receptors: a polypeptide chain traverses the membrane seven times, the extracellular terminal (NH2), the intracelullar carboxyl terminal, sites for binding ligands, G-protein
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
RECEPTOR
G PROTEIN - trimer, , , subunits subunit: GDPGTP, GTPase aktivity
stimulation (GS) , inhibition (GI) of the effector
EFFECTOR
betagama
EFFECTOR
AlfaGDPGTP
AlfaAlfaGTPGTP
AlfaGDP
EFFECTOR RECEPTORG-PROTEIN
AlfaGDP
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
eg. adenylyl cyclase
Gs beta-adrenergic receptor
Gi mu opioid receptor
AlfaGDP
EFFECTOR
EFFECTOR
ENZYM
adenylyl cyklase cAMP
fosfolipase C IP3, DAG Pro
tein
kina
ses
G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)
G-PROTEIN
RECEPTOR
Ca++ release
2nd messengers:
Activation/inhibition of cellular functionseg. contractile proteins, enzymes, transporters, ion channels
ION CHANNEL
Molecular Targets For Drug Action)
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
2. ION CHANNELS
• voltage-gated channels
calcium channels - Ca++ flows into cells, calcium channel blockers
sodium channels - Na++ flows into cells, blocked by local anaesthetics
ligand-gated channels, G protein-gated*, and other*(directly or by intermediaries),
Molecular Targets For Drug Action
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
3. CARRIER MOLECULES
• „pumps“
sodium pump - Na+/K+ ATPase,
„pumps“ Na+ from the cell, inhibited by cardiac glycosides
proton pump - H+/K+ ATPase,
„pumps“ H+ from the cell , proton pump inhibitors
• transporters transporters for noradrenaline, serotonine inhibited by most antidepressants (RUI, TCA, SSRI etc)
Molecular Targets For Drug Action
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
4. ENZYMESsites of action of about 30% of drugs
Drugs inhibiting the enzyme:
Cholinesterase Cholinesterase Inhibitors
Cyclo-oxygenase Non-Steroid Antiinflammatory Drugs
Monoamine oxidase IMAO
Angiotensin- converting enzyme
ACE Inhibitors
HMG-CoA reduktase Statins
and other
G-protein coupled receptorsmembr.
Voltage gated- Calcium chan.
- Sodium chan.
„pumps“- sodium
- proton
transporters
cardiac glykosides
PP inhibitors
lok. anaesthetetics
Calcium ch. blockers
about 45% of drugs,e.g. beta-blockers
antidepressants
ACE inhibitors, IMAO
perif. muscle relaxants
Examples of drugs::
Enzyme-linked rec.intracelul.
Ligand-gated, G-prot.,…
ACE, MAO, COX, HMG-CoA reductase
Channel-linked receptors
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
Molecular mechanisms of drug effects - summaryFOUR MAJOR TARGETS FOR DRUGS:
4. ENZYMES