Transcript Marlboro 100`s Filter Box Red AMMONIUM HYDROXIDE

HO
N
CH3
O
N
N CH
3
HO
morphine
morphine
nicotine
Bi 1 Lecture 2
Tuesday, March 28, 2006 Revised 4/4/06
What is a drug?
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
Trivial names and Structural Formulas
nicotine
(Nestler Fig. 12-4)
procaine
(Nestler p. 50)
H3CH 2C
N
morphine
(Nestler Fig. 16-3)
botulinum toxin
(Nestler p. 203, 323)
CH 2CH 3
H2C
HO
CH 2
N
CH 3
N
O
O
C O
N CH
3
HO
morphine
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
H3CH 2C
Charged amine: may bind
to charged groups on the
protein
+ CH CH
2
3
HN
H2C
Ester: hydrolyzed to
terminate drug action
CH 2
O
C O
Aromatic: may bind
to nonpolar groups
on the protein
NH 2
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Atomic-scale Structures
H3CH 2C
N
morphine
procaine
nicotine
CH 3
N
N
CH 2CH 3
H2C
botulinum
toxin
HO
O
CH 2
N CH
3
O
C O
HO
morphine
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
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Formulas and molecular weights (MW)
morphine
nicotine
procaine
C10H14N2
C13H20N2O2
C17H19N2O3
162
236
285
botulinum
toxin
~150,000
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Trademark Names
nicotine
Marlboro®
(Philip Morris);
procaine
morphine
Novocain®
(Sanofi)
none
botulinum
toxin
BOTOX®
(Allergan)
Nicorette®
(SmithKline
Beecham)
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Type of Compound
morphine
nicotine
alkaloid
(Alkaloids are a group of nitrogenous organic compounds
that have physiological effects on humans).
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Type of Compound
procaine
local anesthetic
(Synthetic organic compound)
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Type of Compound
botulinum
toxin
protein:
Chain of amino-acid residues joined by peptide bonds
11
Routes into the Nervous System
nicotine
procaine
Smoked;
Injected
chewed;
morphine
botulinum
toxin
Injected;
Injected;
suppository
eaten
skin patch
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often the active
and predominant form
H+
RNH3+
RNH2
blood
Lipid barrier,
e. g. membrane(s)
mouth, stomach or lungs
H+
RNH2
RNH3+
higher pH
13
Tobacco leaves are roughly 5% nicotine by weight.
Other ingredients in Marlboro:
http://www.philipmorrisusa.com/en/product_facts/ingredients/brand_by_brand_ingredients.asp
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nicotine: uptake through the lungs
N
CH 3
N
H+
N
blood
pKa = 8.0
CH 3
NH +
Lipid barrier,
e. g. membrane(s)
lungs
N
CH 3
N
pKa = 8.0
H+
N
CH 3
NH +
volatilized form
Marlboro 100's Filter Box Red
AMMONIUM HYDROXIDE
maintains neutral pH
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Marlboro 100's Filter Hard Pack Red
keeps the
cigarette moist
flame retardant
keeps nicotine
neutral
Tobacco
Water
Sugars (Sucrose, Invert Sugar, or Corn
Syrup)
Glycerol
Propylene Glycol
Cocoa & Cocoa Products
Licorice Extract
Diammonium Phosphate
Ammonium Hydroxide
Natural & Artificial Flavors
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Review of nicotine’s path from the lungs to the blood and the brain
N
CH3
N
N
H+
H3C
H
+
N
blood
and brain
cells and membranes
lungs
N
N
CH3
N
H+
H3C
H
+
N
vaporized
Marlboro 100's Filter Box Red
AMMONIUM HYDROXIDE
removes H+
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Blood nicotine concentrations during and after a cigarette
100
nM
80
60
40
20
smoking
0
0
50
100
150
min
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nicotine: uptake through the mouth and skin
Nicorette Website
http://nicorette.quit.com/
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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
catalytic protein
Greek, “to leaven”
HO
H2
C
NH 3
CO 2
HO
levodopa, “L-dopa”
zwitterionic
permeates into brain
+
enzyme:
decarboxylase
HO
-
H2
C
C
H2
NH 3+
HO
dopamine
does not enter brain
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Endothelial cells form the blood-brain barrier
Brain
“Tight junction”
Other organs
~ 10 mm
Protein
Nonpolar molecule
Polar molecule (e. g., glucose)
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Endothelial cells form the blood-brain barrier
Blood vessel
Blood
Glial foot
“Tight junction”
Endothelial cells lining the capillary
Red blood cells
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The Structural Basis
of
Tight Junctions
extracellular
space
Little Alberts, 2nd ed
Figure 21-22
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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
Lecture 5
Neurotransmitter transport inhibitors
Blood-brain barrier:
molecular basis
an opportunity for drug specificity
a problem for drug delivery
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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.
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First uses
procaine
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.
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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.
Morpheus, Greek God of dreams
“poppy that brings sleep”
Genus species
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
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First medical use
botulinum
toxin
1970’s
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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.
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Botulinum toxin is made as a single protein chain, then cleaved
The light chain enters cells,
then acts as an enzyme
catalytic protein
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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.
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http://www.botox.com/
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http://www.beautifulandhealthy.com/
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http://www.stoutlaser.com/botox.html
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