1 Bi 1 Lecture 2 Tuesday, March 28, 2006 Revised 4/4/06 What is a drug? nicotinemorphine.
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Transcript of 1 Bi 1 Lecture 2 Tuesday, March 28, 2006 Revised 4/4/06 What is a drug? nicotinemorphine.
1
Bi 1 Lecture 2
Tuesday, March 28, 2006 Revised 4/4/06
What is a drug?
N
O
HO
HOCH3
morphine
N
CH3N
nicotine morphine
2
drugnoun Pronunciation: 'dr&g Etymology: Middle English droggeDate: 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
3
nicotine(Nestler Fig. 12-4)
N
CH3N
procaine(Nestler p. 50)
O
CH2
H2C
NH2
C O
NH3CH2C CH2CH3
Trivial names and Structural Formulas
botulinum toxin(Nestler p. 203, 323)
N
O
HO
HOCH3
morphine
morphine(Nestler Fig. 16-3)
4
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)
5
Each moiety in a drug molecule has importance.Example: procaine
O
CH2
H2C
NH2
C O
HNH3CH2C CH2CH3
+
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
6
nicotine procaine
N
CH3N
O
CH2
H2C
NH2
C O
NH3CH2C CH2CH3
botulinum toxin
Atomic-scale Structures
(Download to your computer;Then open with Swiss-prot pdb viewer)
N
O
HO
HOCH3
morphine
morphine
http://www.its.caltech.edu/~lester/Bi-1/nicotine.pdb
http://www.its.caltech.edu/~lester/Bi-1/procaine.pdb
http://www.its.caltech.edu/~lester/Bi-1/morphine.pdb
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nicotine procaine botulinum toxin
C13H20N2O2
236
Formulas and molecular weights (MW)
C10H14N2
162~150,000
morphine
C17H19N2O3
285
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nicotine procaine
Novocain®(Sanofi)
Trademark Names
botulinum toxin
BOTOX®(Allergan)
Marlboro®(Philip Morris);
Nicorette®(SmithKlineBeecham)
morphine
none
9
nicotine
Type of CompoundType of Compound
morphine
(Alkaloids are a group of nitrogenous organic compounds
that have physiological effects on humans).
alkaloid
10
procaine
Type of Compound
local anesthetic
(Synthetic organic compound)
Type of Compound
11
botulinum toxin
Type of Compound
protein:
Chain of amino-acid residues joined by peptide bonds
Type of Compound
12
nicotine
Routes into the Nervous System
Smoked;
chewed;
skin patch
procaine
Injected
botulinum toxin
Injected;
eaten
morphine
Injected;
suppository
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blood
mouth, stomach or lungs
RNH2 RNH3+
H+
RNH2 RNH3+
H+
often the active and predominant form
higher pH
Lipid barrier,e. g. membrane(s)
14
Tobacco leaves are roughly 5% nicotine by weight.
http://www.philipmorrisusa.com/en/product_facts/ingredients/brand_by_brand_ingredients.asp
Other ingredients in Marlboro:
16
nicotine: uptake through the lungs
N
CH3N
NH+
CH3N
H+
blood
lungs
N
CH3N
volatilized form
NH+
CH3N
H+
pKa = 8.0
pKa = 8.0
Marlboro 100's Filter Box RedAMMONIUM HYDROXIDE maintains neutral pH
Lipid barrier,e. g. membrane(s)
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Marlboro 100's Filter Hard Pack Red
TobaccoWater
Sugars (Sucrose, Invert Sugar, or Corn Syrup)
GlycerolPropylene Glycol
Cocoa & Cocoa ProductsLicorice Extract
Diammonium PhosphateAmmonium Hydroxide
Natural & Artificial Flavors
keeps the cigarette moist
flame retardant
keeps nicotine neutral
18
Review of nicotine’s path from the lungs to the blood and the brain
N+H3C
N H
H+
vaporizedN
CH3N
Marlboro 100's Filter Box RedAMMONIUM HYDROXIDE removes H+
N
CH3N
H+ N+H3C
N H
bloodand brain
lungs
cells and membranes
19
0
20
40
60
80
100
0 50 100 150
min
nM
Blood nicotine concentrations during and after a cigarette
smoking
20
nicotine: uptake through the mouth and skin
http://nicorette.quit.com/
Nicorette Website
21
levodopa, “L-dopa”zwitterionic
permeates into brain
dopamine
does not enter brain
enzyme:decarboxylase
catalytic protein Greek, “to leaven”
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
H2C NH3
+
CO2-
HO
HO
H2C
CH2
NH3+
22
Brain Other organs
Protein
Nonpolar molecule
Polar molecule (e. g., glucose)
Endothelial cells form the blood-brain barrier
“Tight junction”
~ 10 m
23
Endothelial cells lining the capillary
Red blood cells
Endothelial cells form the blood-brain barrier
“Tight junction”
Blood vessel
Blood
Glial foot
24
The Structural Basis of
Tight Junctions
Little Alberts, 2nd edFigure 21-22
extracellularspace
25
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
Drugs in the Body and in Cells in Bi 1
Lecture 5
26
nicotine
First uses
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.
27
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.
First uses
28
morphine
The first recorded reference to the opium poppy, Papaver somniferum was by a Greek writer in the 3rd Century BC.
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
Greek, “juice”
“poppy that brings sleep”Genus species
Morpheus, Greek God of dreams
First uses
29
botulinum toxin
First medical use
1970’s
30
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.
31
Botulinum toxin is made as a single protein chain, then cleaved
catalytic protein
The light chain enters cells,then acts as an enzyme
32
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.
33
http://www.botox.com/
34
Dr. Mirabadi Cosmetic Surgeon.URL
http://www.beautifulandhealthy.com/
35
Warren C. Stout, M.D. - Cosmetic Eye Surgery and Cosmetic Face Surgery.url
http://www.stoutlaser.com/botox.html