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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

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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

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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)

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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)

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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

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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

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nicotine

Type of CompoundType of Compound

morphine

(Alkaloids are a group of nitrogenous organic compounds

that have physiological effects on humans).

alkaloid

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procaine

Type of Compound

local anesthetic

(Synthetic organic compound)

Type of Compound

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botulinum toxin

Type of Compound

protein:

Chain of amino-acid residues joined by peptide bonds

Type of Compound

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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)

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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:

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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

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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

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0

20

40

60

80

100

0 50 100 150

min

nM

Blood nicotine concentrations during and after a cigarette

smoking

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nicotine: uptake through the mouth and skin

http://nicorette.quit.com/

Nicorette Website

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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+

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Brain Other organs

Protein

Nonpolar molecule

Polar molecule (e. g., glucose)

Endothelial cells form the blood-brain barrier

“Tight junction”

~ 10 m

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Endothelial cells lining the capillary

Red blood cells

Endothelial cells form the blood-brain barrier

“Tight junction”

Blood vessel

Blood

Glial foot

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The Structural Basis of

Tight Junctions

Little Alberts, 2nd edFigure 21-22

extracellularspace

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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

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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.

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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

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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

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botulinum toxin

First medical use

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

catalytic protein

The light chain enters cells,then acts as an enzyme

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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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Dr. Mirabadi Cosmetic Surgeon.URL

http://www.beautifulandhealthy.com/

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Warren C. Stout, M.D. - Cosmetic Eye Surgery and Cosmetic Face Surgery.url

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