© 2013 California Institute of Technology

“Drugs and the Brain”

Week 1 miniLecture 1

Organization and Overview of Weeks 1 – 3 (The Basic Science)

1

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

2

Introducing the Central Nervous System

Brain

Spinal cord

Front“rostral”

Back“caudal”

Bottom “ventral”

Top “dorsal”

3

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

4

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)

6

Week 2: Drugs Activate Ion Channels

Swivel?Miyazawa & Unwin, Nature 2003

~ 100 Å(10 nm)

acetylcholine or

nicotine

acetylcholine or

nicotine

7

Week 2: Drugs Block Ion Channels

Drug

Receptor

current

time

8

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

11

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

12

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

13

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)

15

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

16

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

20

“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