Organic Chemistry

1210 CHAPTER 30 The Organic Chemistry of Drugs

Morphine, the most widely used analgesic for severe pain, is the standard by

which other painkilling medications are measured. Although scientists have learned

how to synthesize morphine, all commercial morphine is obtained from opium, the

juice from a species of poppy. Morphine occurs in opium to the extent of 10%.

Methylating one of the OH groups of morphine produces codeine, which has one-

tenth the analgesic activity of morphine. Codeine profoundly inhibits the cough re-

flex. Although 3% of opium is codeine, most commercial codeine is obtained by

methylating morphine. Esterifying one of the OH groups of morphine produces a

compound with a similar reduced potency. Acetylating both OH groups forms heroin,

which is much more potent than morphine. Heroin is less polar than morphine, so it

crosses the blood–brain barrier more rapidly, resulting in a more rapid “high.”Hero-

in has been banned in most countries because it is widely abused. It is synthesized by

using acetic anhydride to acetylate morphine. Therefore, both heroin and acetic acid

are formed as products. Drug enforcement agencies use dogs trained to recognize the

pungent odor of acetic acid.

Molecular modification of codeine led to dextromethorphan, the active ingredi-

ent in most cough medicines. Etorphine was synthesized when scientists realized

that analgesic potency was related to the drug’s ability to bind hydrophobically to

the opiate receptor (Section 30.6). Etorphine is about 2000 times more potent than

morphine, but it is not safe for use by humans. It has been used to tranquilize

elephants and other large animals. Pentazocine is useful in obstetrics because it

dulls the pain of labor, but does not depress the respiration of the infant as

morphine does.

Methadone was synthesized by German scientists in 1944 in an attempt to find a

drug to treat muscle spasms. (It was originally called “Adolphile”in honor of Adolph

Hitler.) It was not recognized until 10 years later—after building molecular models—

that methadone and morphine have similar shapes. In contrast to morphine,

methadone can be administered orally. Methadone has a considerably longer half-life

(24–26 hours) than morphine (2–4 hours). Cumulative effects are seen with repeated

doses of methadone, so lower doses and longer intervals between doses are possible.

Consequently, methadone is used to treat chronic pain and the withdrawal symptoms

of heroin addicts. Reducing the carbonyl group of methadone and acetylating it forms

a-acetylmethadol. The levo 1 - 2 isomer of this compound can suppress withdrawal

NCH 3

OH

H

OH

HH

HO O

NCH 3

CH 3 O O

NCH 3

CH 3 CO

O O

O OCCH 3

morphine codeine heroin

NCH 3

CH 3 O

NCH 3

HO OCH 3

O

NCH 2 CH

HO

CH 3

CH 3

CCH 2 CH 2 CH 3

OH

CCH 3

CH 3

CH 3

dextromethorphan etorphine pentazocine

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