Organic Chemistry

1216 CHAPTER 30 The Organic Chemistry of Drugs

has the same imidazole ring as 4-methylhistidine, but it has a sulfur atom

and a functional group based on guanidine (Section 23.1). has a different het-

erocyclic ring, and although its side chain is similar to that of it does not

contain a guanidino group.

Observations that serotonin was implicated in the generation of migraine attacks

led to the development of drugs that bind to serotonin receptors. Sumatriptan, intro-

duced in 1991, relieved not only the pain associated with migraines, but also many of

migraine’s other symptoms, including sensitivity to light and sound and nausea.

The success of sumatriptan spurred a search for other antimigraine agents by molecular

modification, and three new triptans were introduced in 1997 and 1998. These

second-generation triptans showed some improvements over sumatriptan—specifically,

a longer half-life, reduced cardiac side effects, and improved CNS penetration.

In screening modified compounds, it is not unusual to find a compound with a com-

pletely different pharmacological activity than the lead compound. For example, a

molecular modification of a sulfonamide, an antibiotic, led to tolbutamide, a drug with

hypoglycemic activity (Section 25.8).

a sulfonamide

H 2 NNHRS

O

O

S

O

O

H 3 C NH C NHCH 2 CH 2 CH 2 CH 3

O

tolbutamide

HO

H

N

CH 2 CH 2 NH 2

serotonin

H

N

CH 2 CH 2 NCH 3

CH 3

sumatriptan

Imitrex

CH 3 NH S

O

O

Tagamet®,

Zantac®

Tagamet®

Tutorial:

Structural similarities in classes

of drugs

NHCH 3 CH 2 SCH 2 CH 2 NH NHCH 3

N

N

H

CH 2 CH 2 NH 3

NO 2

CH 3

+

+

+

CN

C

C

HH

N

C

CH 3 NHCH 2 O

CH 3

4-methylhistamine

cimetidine

Tagamet

ranitidine

Zantac

N

N

H

CH 2 SCH 2 CH 2 NH

CH 3

O

O

H

H N

N

CH 2 CH 2 NCH 3

CH 3

zolmitriptan

Zomig

H

N

NCH 3

naratriptan

Amerge

H

N

N

N

CH 2 CH 2 NCH 3

CH 3

rizatriptan

Maxalt

N

CH 3 NH S

O

O

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