Organic Chemistry

Drugs that interfere with the natural action of histamine—called antihistamines—

bind to the histamine receptor but do not trigger the same response as histamine.

Like histamine, these drugs have a protonated amino group that binds to the receptor.

The drugs also have bulky groups that keep the histamine molecule from approaching

the receptor.

Acetylcholine is a neurohormone that enhances peristalsis, wakefulness, and mem-

ory and is essential for nerve transmission. A deficiency of brain cell receptors that

bind acetylcholine—cholinergic receptors—contributes to the characteristic loss of

memory in Alzheimer’s disease. Cholinergic receptors are structurally similar to those

that bind histamine. Therefore, antihistamines and cholinergic agents show overlap-

ping activities. As a result, the antihistamine diphenhydramine has been used to treat

insomnia and to combat motion sickness.

Excess histamine production by the body also causes the hypersecretion of stomach

acid by the cells of the stomach lining, leading to the development of ulcers. The anti-

histamines that block the histamine receptors—thereby preventing the allergic re-

sponses associated with excess histamine production—have no effect on HCl

production. This fact led scientists to conclude that a second kind of histamine recep-

tor triggers the release of acid into the stomach.

Because 4-methylhistamine was found to cause weak inhibition of HCl secretion, it

was used as a lead compound. About 500 molecular modifications were performed

over a 10-year period before four clinically useful antiulcer agents were found. Two of

these are and Notice that steric blocking of the receptor site is not

a factor in these compounds. Compared with the antihistamines, the effective antiulcer

drugs have more polar rings and longer side chains.

Tagamet® Zantac®.

CH 3 COCH 2 CH 2 N(CH 3 ) 3

+

−

O

acetylcholine

cholinergic

receptor

Section 30.6 Receptors 1215

3-D Molecules:

Histamine;

Diphenhydramine;

Promethazine;

Promazine

CHOCH 2 CH 2 NH(CH 3 ) 2 S NCH 2 CHNH(CH 3 ) 2

CH 3

S NCH 2 CH 2 CH 2 NH(CH 3 ) 2

antihistamines

+ + +

diphenhydramine

Benadryl

promethazine

Promine

promazine

Talofen

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