Organic Chemistry

Coca leaves

Section 30.3 Molecular Modification 1209

30.3 Molecular Modification

A classic example of molecular modification is the development of synthetic local

anesthetics from cocaine. Cocaine comes from the leaves of Erythroxylon coca, a bush

native to the highlands of the South American Andes. Cocaine is a highly effective

local anesthetic, but it produces disturbing effects on the central nervous system

(CNS), ranging from initial euphoria to severe depression. By dissecting the cocaine

molecule step by step—removing the methoxycarbonyl group and cleaving the seven-

membered-ring system—scientists identified the portion of the molecule that carries

the local anesthetic activity without the damaging CNS effects. This knowledge gave

an improved lead compound—an ester of benzoic acid, with the alcohol component of

the ester having a terminal tertiary amino group.

Hundreds of esters were then synthesized, resulting in esters with substituents on

the aromatic ring, esters with the alkyl groups bonded to the nitrogen, and esters with

the length of the connecting alkyl chain modified. Successful anesthetics obtained

through molecular modification were benzocaine, a topical anesthetic, and procaine,

commonly known by the trade name Novocain®.

Because the ester group of procaine is hydrolyzed relatively rapidly by serum ester-

ases (enzymes that catalyze ester hydrolysis), procaine has a short half-life. Therefore,

compounds with less easily hydrolyzed amide groups were synthesized (Section 17.6).

In this way, lidocaine, one of the most widely used injectable anesthetics, was discov-

ered. The rate at which lidocaine is hydrolyzed is further decreased by its two ortho-

methyl substituents, which provide steric hindrance to the vulnerable carbonyl group.

Later, physicians recognized that the action of an anesthetic administered in vivo

(in a living organism) could be lengthened considerably if it were administered along

with epinephrine. Because epinephrine is a vasoconstrictor, it reduces the blood sup-

ply, allowing the drug to remain at its targeted site for a longer period.

In screening the structurally modified compounds for biological activity, scientists

were surprised to find that replacing the ester linkage of procaine with an amide link-

age led to a compound—procainamide hydrochloride—that had activity as a cardiac

depressant as well as activity as a local anesthetic. Procainamide hydrochloride is cur-

rently used clinically as an antiarrhythmic.

H

N

NH 2

O

C

CH 3 CH 2

CH 3 CH 2 Cl−

+NH

procainamide hydrochloride

N

H 3 C

H 3 C

H 3 C

cocaine improved lead compound

lead compound

COOCH 3

O

O

N

C

O

O

C

O O

NH 2

O

C

NH 2

O

C

procaine

Novocain

N

CH 3 CH 2

CH 3 CH 2

CH 3 CH 2

CH 3 CH 2

NH

CH 3

CH 3

O

lidocaine

Xylocaine

N C

Benzocaine

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