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Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General Pharmacology
Lecture: 11th October 2011
8:00-9:30 Jelínek Hall, Ruská 87, Prague
MOLECULAR TARGETS FOR DRUG ACTION
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague
Molecular Targets For Drug Action
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
1. RECEPTORS
J.N. Langley - one of the fathers of the
chemical receptor theory 1905
Channel-linked receptors
G-protein-coupled receptors
Cell Membrane
Cellular
RECEPTORS
Proteinkinase-linked
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
sites for binding ligands, G-protein
Katzung BG, 2009, Fig 2-11
G-PROTEIN-COUPLED RECEPTORS
(„metabotropic receptors“)
M. Rodbell & AG Gilman
1994 Nobel prize
RECEPTOR
G PROTEIN - trimer, alpha, beta, gamma subunits
alpha subunit: GTPase aktivity: GDPGTP,
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
E.W. Sutherland Nobel Prize 1971
G-PROTEIN
adenylyl cyclase  cAMP
2nd messengers:
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
Non-Steroid Antiinflammatory
Drugs
Monoamine oxidase IMAO
Cyclo-oxygenase
Angiotensinconverting enzyme
ACE Inhibitors
HMG-CoA reduktase Statins
and other - e.g. recently
phosphodiesterase
neuroamidase
sildenafil (VIAGRA)
oseltamivir (TAMIFLU)
Renin-Angiotensin-Aldosteron-System
angiotensinogen
aliskiren
renin
Angiotensin I
ACEI
angiotensin converting enzyme
Angiotensin II
Sartans
AT1 receptors
aldosteron
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.
Proteinkinase-linked receptors
c.
- Calcium chan.
Voltage gated
- Sodium chan.
2. ION CHANNELS
imatinib
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
TARGETS FOR BIOLOGICAL TREATMENT
receptors
… monoclonal antibodies e.g.
blocking GPIIb/IIIa receptors on platelets: inhibits platelets aggregation
– abciximab (in percutaneous coronary intervention)
blocking. TNFalfa from binding to TNF receptors
– infliximab (in rheumat.arthritis, psoriasis, Crohn¨s disease)
blocking HER 2 („Human Epidermal growth factor Receptor 2„) receptor
– trastuzumab
genes
(in breast cancers)