Chapter 10 Manipulating Molecules and

Designing Drugs

How are effective drugs designed?

Herbal remedies: Is “natural” safer than synthetic?

How harmful are illicit drugs?

Is our society

becoming

dependent on

prescription drugs?

A wonder drug?

The classic white willow tree, Salix alba, provides more

than just shade and shelter for natures animals.

Salicin is the key ingredient that is isolated from the

tree and converted into one of our most reliable and

heavily used drugs, aspirin!

10.1

White willow tree

It is used as an antipyretic-fever reduction.

It is used as an analgesic-pain

reliever, and as

an anti-inflammatory agent.

salicyn

Semi-synthesis of aspirin: from natural

product to marketed drug

10.1

White willow tree

Possible side effects:

1. Heartburn

2. Nausea

3. Reye’s Syndrom

4. Ringing in ears

5. Rash, itch

6. Shortness of breath

Salicylic

acid

acetic acid

anhydride acetylsalicylic acid

(aspirin)

acetic acid

Would this drug make it

through FDA scrutiny today?

Organic Chemistry –

The Study of Carbon Compounds

There are over 12 million known organic compounds.

Why carbon? Carbon has the remarkable ability to bond

in multiple ways:

10.2

10.2

Some different ways to represent molecular structures:

Structural formula Ball-and-stick formula Space-filling model

10.2

Representing molecular structures with line-angle drawings:

C

C

C

C

C

C

H

HH

H

H

H

H H H

H H

H

H

H

C

C

C C

C

H H

H

H

H

HH

H

H

H

=

=

Each vertex (or end of a line) represents

a carbon with an appropriate number of

hydrogen atoms.

iso hexane, or 2-methyl pentane

cyclopentane

10.2

10.2

Representations of benzene (C6H6), an important

part of many drug molecules.

10.3

Functional groups - arrangements of groups of atoms which

impart characteristic physical and chemical properties.

10.3

More Important Functional groups

The presence and orientation of functional groups are responsible for the action

of all drugs. See Chapter 9 for more info on functional groups.

10.3

Ester Formation

C

O

O

OH

C

O

O CH3

HH

H OH

this O attaches here

This OH and this H form H2O

C

O

O

OH

C

O

CH3

+

Ester functional groups are often found in drugs,

flavorings, and fragrances.

10.3

What are the functional groups in the aspirin molecule?

1. Benzene ring

2. Carboxylic acid

3. Ester

10.3

Salt Formation

The salt forms are often preferred as drugs:

• Increased water solubility

• No odor

• Higher melting points (longer shelf life)

CH CH NH

CH3OH CH3

CH CH NH2Cl-

CH3OH CH3

H Cl+

Pseudoephedrine

freebase Pseudoephedrine

hydrochloride

Functional groups may impart a polar aspect to a

molecule.

A polar molecule has partial charge separation.

d- = “partial negative” d+ = “partial positive”

Examples of polar molecules

10.3

10.4

Hormones, our chemical messengers, are produced by the body’s

endocrine glands.

Hormones encompass a wide range of

functions and a similarly wide range of

chemical composition and structure.

Enzymes are proteins that act as

biochemical catalysts, influencing

the rates of chemical reactions.

Aspirin works by inhibiting the production of certain enzymes

responsible for producing specific hormones.

10.4

Drugs may be broadly classified as:

1. Those that cause a physiological

response in the body.

2. Those that kill foreign invading

organisms.

aspirin

anticancer drugs

morphine

antibiotics

antifungal agents

10.4

Aspirin and other drugs that are physiologically active, but not

antiinfectious agents, are almost always involved in altering the

chemical communication system of the body.

Aspirin, as well as other non-steroidal antiinflammatory (NSAID)

drugs, work by inhibiting the catalytic activity of certain enzymes.

The mode of action is due to the ability of aspirin to block the action

of cyclooxygenase (COX-1 and COX-2) enzymes from producing

the hormonal compounds called prostaglandins.

Certain prostaglandins are responsible for the body’s response to

pain, inflammation, and fever.

10.4

Prostaglandins cause a variety of effects. They produce fever and

swelling, increase sensitivity of pain receptors, inhibit blood vessel

dilation, regulate the production of acid and mucus in the stomach,

and assist kidney functions.

By preventing COX-2 enzymes from catalyzing prostaglandin

production, aspirin reduces fever and swelling. It also suppresses

pain receptors and so functions as a painkiller.

But the drug (as do other NSAIDs) also inhibit COX-1 enzymes

that primarily make hormones that maintain proper kidney

function and keep the stomach lining intact.

Thus, NSAIDs drugs are not sufficiently selective to affect COX-

2 without shutting down COX-1 as well.

10.4

Researchers raced to create nearly a dozen new candidate drugs that

block COX-2 alone. This work resulted in the emergence of a new

class of medicines in the late 1990s called COX-2 inhibitors.

Two wildly popular and heavily prescribed COX-2 inhibitors are

Vioxx and Celebrex. These new “superaspirins” were touted as

being safer and more effective than currently available NSAIDs.

The premise is that since they do not act on the COX-1 enzymes,

there should be fewer gastrointestinal (GI) side effects.

The reality is that they have not been proven to be more effective or

safer than aspirin or ibuprofen. In fact, they have been proven to be

more dangerous than helpful.

Use the Web to write a short essay on the life and death of “super

aspirins.”

10.4

Uncertain future for the COX-2 inhibitors is due to emerging

evidence of their questionable safety. As of 2008, they have been

pulled off the shelf by their manufacturers.

Two COX-2

Inhibitors

10.4

Aspirin, revisited – mode of action

COX enzymes

Prostaglandin production

COX -1: liver function, stomach lining

COX-2: fever, pain sensation,

inflammation

10.5

Drug Discovery-serendipity

Sir Alexander Fleming, British

bacteriologist

Working with Staphylococcus-a

bacteria.

A colleague working in same

building was working with

Penicillium notatum-a fungus

that produces penicillin.

Series of chance occurrences,

and penicillin was discovered. Actual photo of petri dish Flemming showing

inhibition of growth of bacteria where penicillin

landed on the dish.

Drug Discovery-serendipity

S

N

CH3

CH3

COOHO

N

H

PhOCH2

O

Penicillin V

“In the fields of observation, chance favors

only the prepared mind”

-Louis Pasteur

10.5

How many functional groups

can you identify in the structure

above?

The lock and key model.

A substrate is a substance whose reactions

are catalyzed by an enzyme. Here you see

a drug occupying the receptor site of the natural

substrate. 10.5

Drug interactions at the cellular level

10.5

The functional groups and their placement in three-dimensional

space determines to a large degree a molecule’s biological activity.

The portion of a molecule that determines the biological

effects of a drug is called the pharmacophore.

Combinatorial Chemistry

The benefits of using combinatorial chemistry:

1. Many molecules can be created at a rapid rate.

2. The cost of the procedure is much cheaper than traditional molecule

synthesis.

3. Large libraries of bioactive lead compounds can be produced relatively inexpensively

Combinatorial chemistry is the systematic creation of large numbers of small

molecules in “libraries” that can be rapidly screened in vitro for potential new

drugs.

10.5

10.6

Chiral molecules have 4 different groups

attached to a central atom.

A chiral molecule and its non-

superimposable mirror image are a special

kind of isomer called enantiomers.

Enantiomers have identical physical

properties.

The only way we can tell them apart is by

seeing their effect on plane polarized light.

10.6

However, the body can tell them apart. These two

enantiomers may have very different actions in the human

body.

One enantiomer fits into a receptor site, while the other does not. The

molecule on the right will have (possibly) no affect on the human body.

10.6

Consider the two enantiomers above.

Dextromethorphan is a safe cough suppressant.

Levomethorphan is an addictive opiate.

10.7

Function Examples

Regulation of secondary

sexual characteristics

Estradiol (an estrogen); testosterone

(an androgen)

Reproduction and control of

the reproductive cycle

Progesterone and the gestagens

Regulation of metabolism Cortisol; cortisone derivatives

Digestion of fat Cholic acid; bile salts

Cell membrane component Cholesterol

Steroids perform many functions in the body:

A B

C DThis is the basic carbon

skeleton for all steroids.

10.7

Functional groups in some common steroids alcohols

ketones

carboxylic acid

Can you identify

the functional

groups

in the other

examples?

RU-486, The Abortion Pill

RU-486 acts as an antagonist – a drug that fits into a receptor

site, but does not have the customary effect as does another drug;

in this case the other drug is progesterone.

Controversial: how about a

class discussion on the topic?

10.9

Getting a New Drug to Market

On average, the process takes about 12 years and over

$500 million.

Animals and Drug Testing

10.9

Is it morally ethical to test newly developed drugs on animals?

What does the LD50 standard mean?

Provide pros and cons for both sides of the issue of animal testing.

Prescription, Generic, and Over-the-Counter

Medicines

10.10

A generic drug is chemically equivalent to the pioneer drug, but cannot be

marketed until the patent protection on the pioneer drug has run out after 20

years.

The lower priced drug commonly marketed under its generic name, in this

case alprazolam instead of Xanax.

Herbal Remedies

10.11

10.11

Ephedra – used safely for thousands of years as herbal remedy

known as Ma Huang.

In 2003, several deaths related to the ingredients led the FDA

(in 2004) to ban ephedra products. At this time, there are

ongoing discussions to make the product available again.

10.14

Ephedra

The herb contains the amphetamine-like

alkaloids – ephedrine and the less active

pseudoephedrine.

Pseudoephedrene is used as a decongestant

Ephedrine is a bronchodilator (opens the airways), and a stimulant

10.12

Drugs of Abuse

10.12

OxyContin contains oxycodone

But this formulation includes a time-released mechanism for long-lasting

treatment of chronic pain.

Drug abusers quickly determined how to get around the time-release and

were able to rapidly ingest large amounts of oxycodone. The effects were

said to be similar to heroin.

Over-prescribed in the Appalachian areas in late 1990s and early 2000s.

Many became addicted.

Oxycodone has been used

safely for many years.

10.12

Marijuana – Cannabis sativa

THC, or delta-9-tetrahydrocannabinol is the active drug in

marijuana.

Medical uses continue to be argued, the Federal Government is

opposed.

10.12

MDMA or Ecstasy

3,4-methylenedioxy-n-methylamphetamine

Schedule I drug, yet clinical therapists are continuing to argue

its potential benefits as a therapeutic agent.