Download 1. RECEPTORS

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
1. RECEPTORS
Channel-linked receptors
G-protein-coupled receptors
Cell Membrane
Kinase-linked receptors
RECEPTORS
Intracellular - Receptors linked to gene
transcription (nuclear receptors)
CHANNEL-LINKED RECEPTORS
(„ionotropic 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“)
Nicotinic receptor
Katzung 2-12 ale
raději GABAA
Katzung BG, 2001
pentameric structure - five subunits form a cluster
surrounding a central transmembrane pore. When
acetylcholine binds, the channel pore opens.
CHANNEL-LINKED RECEPTORS
(„ionotropic receptors“)
Cl-
GABAA receptor
Benzodiazep. receptor
Cl-
- pentameric structure
- receptor for GABA, for
modulatory drugs (eg.
benzodiazepines)
Remedia 1998
G-PROTEIN-COUPLED RECEPTORS
(„metabotropic receptors“)
- 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“)
Katzung Fig 2-14
serpentine receptors: a polypeptide chain
traverses the membrane seven times, the
extracellular terminal (NH2), the
intracelullar carboxyl terminal, sites for
binding ligands, G-protein
Katzung BG, 2001
G-PROTEIN-COUPLED RECEPTORS
(„metabotropic receptors“)
RECEPTOR
G PROTEIN - trimer, , ,  subunits
 subunit: GDPGTP, GTPase aktivity
stimulation (GS) , inhibition (GI) of the effector
EFFECTOR
G-PROTEIN-COUPLED RECEPTORS
(„metabotropic receptors“)
EFFECTOR
RECEPTOR
G-PROTEIN
Alfa
Alfa
GTP
GDP
Alfa
GDPGTP
eg. adenylyl cyclase
Gs beta-adrenergic receptor
Gi mu opioid receptor
Alfa betagama
GDP
G-PROTEIN-COUPLED RECEPTORS
(„metabotropic receptors“)
RECEPTOR
G-PROTEIN
2nd messengers:
adenylyl cyklase  cAMP
ENZYM
EFFECTOR
fosfolipase C IP3, DAG
ION CHANNEL
Ca++ release
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. ENZYMES
sites of action of about 30% of drugs
Drugs inhibiting the enzyme:
Cholinesterase
Cholinesterase Inhibitors
Cyclo-oxygenase
Non-Steroid Antiinflammatory
Drugs
IMAO
Monoamine oxidase
Angiotensinconverting enzyme
ACE Inhibitors
HMG-CoA reduktase
Statins
and other
Molecular mechanisms of drug effects - summary
FOUR MAJOR TARGETS FOR DRUGS:
Examples of drugs::
Channel-linked receptors perif. muscle relaxants
membr.
about 45% of drugs,e.g.
G-protein coupled receptors beta-blockers
1. RECEPTORS
intracelul.
Enzyme-linked rec.
- Calcium chan.
Voltage gated
- Sodium chan.
2. ION CHANNELS
Calcium ch. blockers
lok. anaesthetetics
Ligand-gated, G-prot.,…
„pumps“
3. CARRIER MOLECULES
- sodium
cardiac glykosides
- proton
PP inhibitors
transporters
4. ENZYMES
ACE, MAO, COX, HMG-CoA reductase
antidepressants
ACE inhibitors, IMAO