2014 slides week1 d b organization
TRANSCRIPT
© 2013 California Institute of Technology
“Drugs and the Brain”
Week 1 miniLecture 1
Organization and Overview of Weeks 1 – 3 (The Basic Science)
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nicotinePubchem 89594
lidocainePubchem 3676
botulinum toxinPDB 1S0G
morphinePubchem 5288826
What’s a Drug?
N
NCH3
N
O
HO
CH3
morphineHO
HH
C
HN
N
H3C CH3
H3C CH3
O
Pubchem is an NIH database; PDB (“Protein Data Bank”) files are curated by an international organization
We don’t use trademarks; they vary by country and by preparation
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Introducing the Central Nervous System
Brain
Spinal cord
Front“rostral”
Back“caudal”
Bottom “ventral”
Top “dorsal”
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presynaptic neuronpostsynaptic neuron
The synapse is a point of information processing
An adult human brain contains ~ 1011 neurons,
and each of these might receive 103 synapses apiece,
for a total of 1014 synapses.
Most of these synapses form during the first 2 yr of life.
Thus 1014 synapses / 108 s = 106 synapses/s form in a fetus and infant!
Box 2 - 2 Figure A
Nestler, Hyman, Malenka, Molecular Neuropharmacology,© McGraw-Hill Professional Publishing
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Binding region
Membrane region
Cytosolicregion
Colored by secondary
structure
Colored by subunit(chain)
Most drug receptors are membrane proteins (Nicotinic Acetylcholine Receptor)
~ 2200 amino acids in 5 chains
(“subunits”),
MW ~ 2.5 x 106
PDB 2BG9 5
Drug receptors are proteins. Here’s the acetylcholine binding protein interfacial “aromatic box” occupied by nicotine
Y198C2
Y190C1
Y93A
W149B
non-W55D
(Muscle Nicotinic numbering)
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Week 2: Drugs Activate Ion Channels
Swivel?Miyazawa & Unwin, Nature 2003
~ 100 Å(10 nm)
acetylcholine or
nicotine
acetylcholine or
nicotine
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Week 2: Drugs Block Ion Channels
Drug
Receptor
current
time
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Plasma Membrane Components of the G Protein Pathway
GTP GDP + Pi
Effector: enzyme or channel
outside
Neurotransmitter or hormonebinds to receptor
activatesG protein
How fast?100 ms to 10 s
How far?Probably less 1 m
inside
Rasmussen et al., Nature 2011PDB file 3SN6
Week 3: Drugs Act on G protein pathways
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Alberts et al., Essential Cell Biology, © Garland Science
Downstream from GPCRs are intracellular messengers. We have several ways to measure them.
Live-cell imaging is one way. Biochemistry is another.
Fluorescence Microscopy
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Antidepressants (“SSRIs” = Selective serotoninreuptake inhibitors):
Drugs of abuse: MDMA
Attention-deficit disorder medications:amphetamines
Drugs of abuse: cocaine amphetamines
Na+-coupledcell membrane serotonintransporter
Na+-coupledcell membrane dopamine transporter
NH
HO NH3+
HO
HOH2C
CH2
NH3+
cytosol
outside
Presynapticterminals
Week 3: Drugs Act on Transporters
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Week 3: Dose-response relations
levodopa, “L-dopa”zwitterionic
permeates into brain
dopaminedoes not enter brain
enzyme:decarboxylase
HO
HO NH3+
CO2-
HO
HO NH3+
Week 3: Pharmacokinetics
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NH2
CH3
amphetamine
H3C
H2C
OHethanol
N
N N
N
O
O
H3C
CH3
CH3
caffeine
Week 3: Recreational drugs Addictive drugs Abused drugs Illegal drugs
N
NCH3
nicotine
N
O
HO
CH3
morphineHO
HH
OH3CH3C
CH3
OH
C5H11
tetrahydrocannabinol
H
H
NHH3C
O
Cl
S-ketamine
N
O
CH3
O
CH3cocaine
O
O
HH3C
H3C
H3C
N
O
NH
N
LSD
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Please see two items on the course’s Web page:
Henry Lester’s sources of research funding; and the disclaimer about medical advice
“Drugs and the Brain”
End of miniLecture 1, Week 1
© 2013 California Institute of Technology 14
© 2013 California Institute of Technology
“Drugs and the Brain”
Week 1 miniLecture 2
Organization and Overview of Weeks 4 -7 (Drugs for Neural Diseases)
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kinase
phosphorylatedprotein
cAMPCa2+
intracellularmessenger
receptor
tsqiG protein
enzymechannel effector
NMDA receptors
and
nAChRs
are highly permeable to Ca2+
as well as to Na+.
Possible molecular mechanism for changes with chronic nicotine:
Signal transduction triggered by a ligand-gated channel
Brunzell, Russell, & Piccotto, J. Neurochem, 2003
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Week 4: Drug Addiction and Abuse
Neurons that Make Dopamine Die in Parkinson’s Disease
Figure 8-6
Nestler, Hyman, Malenka, Molecular Neuropharmacology,© McGraw-Hill Professional Publishing
Week 5. Drugs for neurodegenerative diseases
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Week 6. Drugs for Epilepsy and Migraine
Migraine
Figure 18-4
Nestler, Hyman, Malenka, Molecular Neuropharmacology,© McGraw-Hill Professional Publishing
sumatriptan
H3CHN
SO
O
HN
NH3C
CH3
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Some psychiatric drugs, their targets, logP values, half lives, and receptors
fluoxetine serotonin transporter
logP 3.4, 24-72 hr
clozapine 5-HT2A serotonin receptor, GPCR
logP 3.2, 8-12 hr
S-ketamine NMDA glutamate receptor
logP 2.2, 3-5 hr
chlorpromazine dopamine D2 receptor, GPCR
logP 5.2, 16-30 hr
nicotine acetylcholine receptor
logP 1.2, 0.5 -2 hr
recreational / abused / addictive
antipsychoticantidepressant
Weeks 6 and 7. Drugs for psychiatric diseases
diazepamGABAA receptor
logP 3, 1 hr
N
N
O
Cl
anxiolytic
N
S
N Cl
NH O
ClHN
N
N
N
Cl
NH
O
FFFN
N CH3
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1887 1887-88
Bipolar Disease
Vincent Van Gogh 1853-1890750 paintings; 1600 drawings; 700 letters
Life history: born and raised in the Netherlands. Paris 1886-88Arles 1888 (1st episode; cut off his own ear); hospitalized 1888-1890Auvers-sur-Oise 3 months. Shot himself 7/27/1890
1886
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“He saw the world in a way no one could have imagined.”
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Eroom’s law applies especially to neural drugsScannell, Nature Revs Drug Disc. 2012
Week 7. Drug Development for the CNS
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Contemporary ideas about psychiatric drugshave emphasized binding to
the classical targets at synapses. . . “Inside-out” mechanisms emphasize binding to
the same classical targets, but within the endoplasmic reticulum and cis-Golgi
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“Drugs and the Brain”
End of miniLecture 2, Week 1
© 2013 California Institute of Technology 24