Transcript molecular targets for drug action

Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General Pharmacology
Lecture: 31th October 2012
8:00-9:30 Burian Hall, Ruská 87, Prague
MOLECULAR TARGETS FOR DRUG ACTION
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague
Teaching Unit No. 9: Molecular targets for drug action
http://vyuka.lf3.cuni.cz/
Molecular Targets For Drug Action
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
Cellular basis of medicine
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
R.J. Lefkowitz & B.K. Kobilka
2012 Nobel prize
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
ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP).
EFFECTOR
G-PROTEIN-COUPLED RECEPTORS (GPCR)
(„metabotropic receptors“)
When a ligand binds to the GPCR it causes a conformational change in the GPCR
EFFECTOR
GPCR
RECEPTOR
G-PROTEIN
Alfa
Alfa
GTP
GDP
Alfa
GDPGTP
Alfa betagama
GDP
The GPCR can then activate an associated G-protein alpha subunit by exchanging its bound GDP for a GTP
eg. adenylyl cyclase
Gs adenylyl cyclase in beta-adrenergic receptor
Gi adenylyl cyclase in mu opioid receptor
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
sildenafil (VIAGRA)
degradating cGMP
neuroamidase
oseltamivir (TAMIFLU)
stops the virus from chemically
cutting ties with its host cell
Renin-Angiotensin-Systém (RAS)
system that regulates blood pressure and water (fluid) balance
angiotensinogen
aliskiren
renin
Angiotensin I
causes blood vessels to constrict,
ACEI
angiotensin converting enzyme
Angiotensin II
Sartans
AT1 receptors
aldosteron
increases the reabsorption of sodium and
water in the kidney
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
Teaching Unit No.
(PVJ)
http://vyuka.lf3.cuni.cz
PRACTICALS
10
Drugs acting via dopamine, serotonin, histamine
16
Drugs acting via ion channels and transporters
Week
5
8
18
Drugs acting via enzymes
9
22
Drugs acting via nitric oxide, peptides .
11
30
Overview of molecular mechanisms of drug
effects
15
TARGETS FOR BIOLOGICAL TREATMENT
receptors
… antibodies e.g.
blocking glycoprotein GPIIb/IIIa receptors on platelets: inhibits platelets
aggregation
– abciximab (in percutaneous coronary intervention)
monoclonal antibodies:
blocking tumour necrosis factor 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 (in breast cancers)