Drugs and the Brain

Week 1 miniLecture 1
Organization and Overview of Weeks 1 3 (The Basic Science)
2013 California Institute of Technology

Whats a Drug?
We dont use trademarks; they vary by country and by preparation
nicotine
Pubchem 89594

lidocaine
Pubchem 3676
H 3C

morphine
Pubchem 5288826

botulinum toxin
PDB 1S0G

CH3
HO

CH3

C O
HN
H 3C

H
N CH
3

HO

CH3

morphine

Pubchem is an NIH database;

PDB (Protein Data Bank) files are curated by an international organization
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Introducing the Central Nervous System

Top dorsal
Front
rostral

Back
caudal

Brain

Bottom ventral

Spinal cord

The synapse is a point of information processing

presynaptic neuron
postsynaptic neuron

Nestler, Hyman, Malenka, Molecular Neuropharmacology,

McGraw-Hill Professional Publishing

Box 2 - 2 Figure A

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!
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Most drug receptors are membrane proteins (Nicotinic Acetylcholine Receptor)

~ 2200
amino acids
in 5 chains
(subunits),

Binding
region

MW
~ 2.5 x 106

Membrane
region

Colored by
secondary
structure

Colored by
subunit
(chain)

PDB 2BG9

Cytosolic
region

Drug receptors are proteins.

Heres the acetylcholine binding protein interfacial aromatic box occupied by nicotine

Y198
C2

W149
B

Y93
A

Y190
C1

non-W55
D

(Muscle Nicotinic numbering)

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Week 2: Drugs Activate Ion Channels

~ 100
(10 nm)

acetylcholine
or
nicotine

acetylcholine
or
nicotine

Swivel?
Miyazawa & Unwin, Nature 2003
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Week 2: Drugs Block Ion Channels

Drug
Receptor

current

time

Week 3: Drugs Act on G protein pathways

Plasma Membrane Components of the G Protein Pathway
How far?
How fast?
100 ms to 10 s Probably less 1 m
Neurotransmitter or hormone
binds to receptor
activates
G protein

Effector:
enzyme or channel
outside

Rasmussen et al.,
Nature 2011
PDB file 3SN6

GTP

inside

GDP + Pi
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Downstream from GPCRs are intracellular messengers.

We have several ways to measure them.
Live-cell imaging is one way. Biochemistry is another.
Fluorescence
Microscopy

Alberts et al., Essential Cell Biology,

Garland Science

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Week 3: Drugs Act on Transporters

Antidepressants
(SSRIs =
Selective serotonin
reuptake inhibitors):

Attention-deficit
disorder medications:
amphetamines

Drugs of abuse:
MDMA

Drugs of abuse:
cocaine
amphetamines
Presynaptic
terminals

Na+-coupled
cell membrane
serotonin
transporter

Na+-coupled
cell membrane
dopamine
transporter
cytosol

NH3+

HO

outside
HO

N
H

HO

H2
C

C
H2

NH3+
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Week 3: Dose-response relations

Response

0.5

0
1

10

100

1,000

10,000

[agonist], nM (log scale)

Week 3: Pharmacokinetics
HO

NH3+
CO2-

HO

levodopa, L-dopa
zwitterionic
permeates into brain

enzyme:
decarboxylase

HO

NH3+

HO

dopamine
does not enter brain
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Week 3: Recreational drugs Addictive drugs Abused drugs Illegal drugs

CH3

HO

H
O

N CH
3

HO

H
H 3C
O
H 3C

H 3C

C5H11

H2
C

OH

ethanol

tetrahydrocannabinol

morphine

H 3C

OH

CH3
N

H3 C

Cl

H3C

NH

H3 C
H
N

NH

N
O

H 3C

CH3
caffeine

S-ketamine

LSD

CH3
N

CH3
N

NH2

CH3

O
O

nicotine

cocaine

amphetamine

CH3
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Please see two items on the courses Web page:

Henry Lesters 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

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Drugs and the Brain

Week 1 miniLecture 2
Organization and Overview of Weeks 4 -7 (Drugs for Neural Diseases)
2013 California Institute of Technology

15

Week 4: Drug Addiction and Abuse

Possible molecular mechanism for changes with chronic nicotine:
Signal transduction triggered by a ligand-gated channel
receptor
G protein
i q s t
effector
channel enzyme
NMDA receptors
and

intracellular
messenger
Ca2+ cAMP

nAChRs

kinase

Brunzell, Russell, & Piccotto,

J. Neurochem, 2003

are highly permeable to Ca2+

phosphorylated
protein

as well as to Na+.

16

Week 5. Drugs for neurodegenerative diseases

Neurons that Make Dopamine Die in Parkinsons Disease

Nestler, Hyman, Malenka, Molecular Neuropharmacology,

McGraw-Hill Professional Publishing

Figure 8-6
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Week 6. Drugs for Epilepsy and Migraine

H 3C

Migraine

H
N

O
S
O

H
N

H 3C

N CH
3

sumatriptan

Nestler, Hyman, Malenka, Molecular Neuropharmacology,

McGraw-Hill Professional Publishing

Figure 18-4
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Weeks 6 and 7. Drugs for psychiatric diseases

Some psychiatric drugs, their targets, logP values, half lives, and receptors
recreational /
abused / addictive

antidepressant

antipsychotic
N

F
F

CH3
N

N
N
H

nicotine
acetylcholine receptor
logP 1.2, 0.5 -2 hr

fluoxetine
serotonin transporter
logP 3.4, 24-72 hr

Cl

chlorpromazine
dopamine D2 receptor, GPCR
logP 5.2, 16-30 hr

anxiolytic
N

Cl

Cl

N
N

NH

H
N

Cl

diazepam
GABAA receptor
logP 3, 1 hr

S-ketamine
NMDA glutamate receptor
logP 2.2, 3-5 hr

clozapine
5-HT2A serotonin receptor, GPCR
logP 3.2, 8-12 hr
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Bipolar Disease
Vincent Van Gogh 1853-1890
750 paintings;
1600 drawings;

700 letters

Life history: born and raised in the Netherlands. Paris 1886-88

Arles 1888 (1st episode; cut off his own ear); hospitalized 1888-1890
Auvers-sur-Oise 3 months. Shot himself 7/27/1890
1886

1887

1887-88

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He saw the world in a way no one could have imagined.

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Week 7. Drug Development for the CNS

Erooms law applies especially to neural drugs
Scannell, Nature Revs Drug Disc. 2012

22

Contemporary ideas about psychiatric drugs

have 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

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