N
CH
3
N nicotine
Bi 1 Lecture 2
Tuesday, March 28, 2006 Revised 4/4/06
What is a drug?
HO
O
HO
N
CH
3
1

drug noun Pronunciation : 'dr&g Etymology : Middle English drogge
Date : 14th century
1 a (obsolete) : a substance used in dyeing or chemical operations b : a substance used as a medication or in the preparation of medication c according to the Food, Drug, and Cosmetic Act
(1) : a substance recognized in an official pharmacopoeia or formulary
(2) : a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease
(3) : a substance other than food intended to affect the structure or function of the body
(4) : a substance intended for use as a component of a medicine but not a device or a component, part, or accessory of a device
2 : a commodity that is not salable or for which there is no demand--used in the phrase,
“drug on the market”
3 : something and often an illegal substance that causes addiction, habituation, or a marked change in consciousness
2

nicotine
(Nestler Fig. 12-4)
Trivial names and Structural Formulas procaine
(Nestler p. 50) morphine
(Nestler Fig. 16-3) botulinum toxin
(Nestler p. 203, 323)
N
CH
3
N
H
3
CH
2
C
N
H
2
C
O
CH
2
CH
2
CH
3
C O
HO
O
HO morphine
N
CH
3
NH
2
3

Today’s drugs exemplify the
“Central Dogma of Drugs and the Brain”
Part 1: Drugs Activate (nicotine) and block (procaine) ion channels
Part 2: Drugs act on G protein pathways (morphine)
Part 3: Drugs activate genes (nicotine, morphine)
Part 4: Protein drugs may be the wave of the future for neuroscience diseases (botulinum toxin)
4

Each moiety in a drug molecule has importance.
Example: procaine
H
3
CH
2
C +
HN
CH
2
CH
3
H
2
C
O
CH
2
C O
Charged amine: may bind to charged groups on the protein
Ester: hydrolyzed to terminate drug action
Aromatic: may bind to nonpolar groups on the protein
NH
2
5

nicotine
N
CH
3
N
Atomic-scale Structures procaine morphine
H
3
CH
2
C
N
H
2
C
CH
2
O
CH
2
CH
3
HO
O
HO
C O morphine
N
CH
3 botulinum toxin
NH
2
(Download to your computer;
Then open with Swiss-prot pdb viewer) http://www.its.caltech.edu/~lester/Bi-1/morphine.pdb
http://www.its.caltech.edu/~lester/Bi-1/procaine.pdb
http://www.its.caltech.edu/~lester/Bi-1/nicotine.pdb
6

nicotine
Formulas and molecular weights (MW) procaine morphine botulinum toxin
C
10
H
14
N
2
162
C
13
H
20
N
2
O
2
236
C
17
H
19
N
2
O
3
285
~150,000
7

nicotine
Marlboro®
(Philip Morris);
Nicorette®
(SmithKline
Beecham)
Trademark Names procaine morphine botulinum toxin
Novocain®
(Sanofi) none
BOTOX®
(Allergan)
8

nicotine morphine alkaloid
(Alkaloids are a group of nitrogenous organic compounds that have physiological effects on humans).
9

procaine local anesthetic
(Synthetic organic compound)
10

protein:
Chain of amino-acid residues joined by peptide bonds botulinum toxin
11

nicotine
Smoked; chewed; skin patch
Routes into the Nervous System procaine morphine
Injected Injected; suppository botulinum toxin
Injected; eaten
12

RNH
2
H +
RNH
3
+ often the active and predominant form blood
Lipid barrier, e. g. membrane(s) mouth, stomach or lungs
RNH
2
H +
RNH
3
+ higher pH
13

Other ingredients in Marlboro: http://www.philipmorrisusa.com/en/product_facts/ingredients/brand_by_brand_ingredients.asp
14

blood lungs volatilized form
N nicotine: uptake through the lungs
CH
3
N pKa = 8.0
H +
N
CH
3
NH
+
Lipid barrier, e. g. membrane(s)
N
CH
3
N pKa = 8.0
H +
N
CH
3
NH
+
Marlboro 100's Filter Box Red
AMMONIUM HYDROXIDE maintains neutral pH
16

keeps the cigarette moist flame retardant keeps nicotine neutral
Marlboro 100's Filter Hard Pack Red
Tobacco
Water
Sugars (Sucrose, Invert Sugar, or Corn
Syrup)
Glycerol
Propylene Glycol
Cocoa & Cocoa Products
Licorice Extract
Diammonium Phosphate
Ammonium Hydroxide
Natural & Artificial Flavors
17

Review of nicotine’s path from the lungs to the blood and the brain
N
CH
3
N
H
+
N
H
3
C
N
+
H blood and brain cells and membranes lungs
N
CH
3
N H
+
N
H
3
C
N
+
H vaporized
Marlboro 100's Filter Box Red
AMMONIUM HYDROXIDE removes H
+
18

Blood nicotine concentrations during and after a cigarette
100
80
60
40
20 smoking
0
0 50 100 150 min
19

nicotine: uptake through the mouth and skin
Nicorette Website http://nicorette.quit.com/
20

Another example of neutral drug permeation.
In Parkinson’s Disease: most neurons that make dopamine die (Lecture 25)
The challenge: replace the dopamine in the brain
HO
HO
H
2
C NH
3
+
CO
2
enzyme: decarboxylase catalytic protein
Greek, “to leaven”
HO
H
2
C
C
H
2
NH
3
+
HO levodopa, “L-dopa” zwitterionic permeates into brain dopamine does not enter brain
21

Brain
Endothelial cells form the blood-brain barrier
“Tight junction”
Other organs
~ 10 m m
Protein
Nonpolar molecule
Polar molecule (e. g., glucose)
22

Blood
Endothelial cells form the blood-brain barrier
Blood vessel
Glial foot
“Tight junction”
Red blood cells
Endothelial cells lining the capillary
23

The Structural Basis of
Tight Junctions extracellular space
Little Alberts, 2 nd
Figure 21-22 ed
24

Drugs in the Body and in Cells in Bi 1
Acid-base equilibrium and permeability
Uptake from the stomach
Uptake from smoke
Crossing the cell membrane
Short-circuiting synaptic vesicles
Neurotransmitter transport inhibitors
Blood-brain barrier: molecular basis an opportunity for drug specificity a problem for drug delivery
Lecture 5
25

First uses nicotine
Ca. 1550
Both the tobacco plant ( Nicotiana tabacum ) and the compound are named for
Jean Nicot, a French ambassador to Portugal, who sent tobacco seeds to Paris in 1550.
26

procaine
First uses
Procaine was synthesized originally in 1905 as a replacement for cocaine.
Cocaine became popular in the late 19th Century both as a stimulant and as an anesthetic. Organic chemists hoped to synthesize compounds that lacked the stimulant effects but retained the anesthetic effects.
Procaine met these goals. It is still used by dentists.
Similar acting compounds: xylocaine, benzocaine.
27

First uses
HO morphine
O
N
CH
3
HO morphine Greek, “juice”
The first recorded reference to the opium poppy, Papaver somniferum was by a
Greek writer in the 3rd Century BC.
“poppy that brings sleep”
Genus species
Morpheus, Greek God of dreams
Morphine was first extracted from the opium poppy in 1806.
There are about 20 other alkaloids in opium.
Structure finally solved by Robert Richardson (Nobel Prize 1947)
Derivatives: heroin, codeine, Fentanyl, methadone
28

First medical use botulinum toxin
1970’s
29

botulinum toxin
Botulinum toxin is made by Clostridium botulinum , an anaerobic bacterium.
“Botulism” comes from a German physician who noticed cases of paralysis associated with eating an uncooked smoked sausage 1793. 13 people in Wildbad shared the sausage that had been sitting for hours; all became ill and six died. (To describe their illness, the word botulism was derived from the Latin botulus , for sausage.)
The conditions beneath the skin of the eaten sausage had been anaerobic (i.e., there was very little oxygen in the meat) and enough time had elapsed to allow the clostridial organisms present to multiply and produce a toxin in the sausage substance.
Botulinum toxin is fatal in extremely low quantities (10 -13 M), because it paralyzes muscles. 10 -8 grams kills a mouse. The paralysis occurs at the synapse.
30

Botulinum toxin is made as a single protein chain, then cleaved
The light chain enters cells, then acts as an enzyme catalytic protein
31

botulinum toxin
However, many diseases and discomforts are caused by excess muscle activity.
Botulinum toxin, injected in minute quantities, blocks this excess activity and gives relief from squint and spasm.
Botulinum toxin also decreases frown lines.
32

http://www.botox.com/
33

34

http://www.stoutlaser.com/botox.html
35