Lengthening of the N-substituent in meperidine leads to active analgesics such as the
propiophenone analog, which is 200 times more active than meperidine. However, the
butyrophenone derivative suddenly becomes a highly active neuroleptic without any
analgesic activity.
Perhaps the most successful modification of the 4-phenylpiperidine derivatives of
morphine is the 4-anilino compounds, such as fentanyl (3.15). This drug is 50–100
times more active than morphine, owing mainly to its excellent transport across the
blood–brain barrier and into the CNS as a result of its high lipophilicity. Spectacular
activities (~ 5000–6000 times that of morphine) have also been achieved by introduc-
ing ether or keto substituents (sufentanil), as in the meperidine or ketobemidone series.
Fentanyl derivatives are very fast acting and of short duration. They are used in neu-
roleptanalgesia in surgery, in combination with neuroleptics or major tranquilizers like
droperidol.
5.18.10 Opiate AntagonistsOpiate addiction affects the life of millions of humans in the Western hemisphere alone.
Since addiction is a potentially serious medical problem, the identification of opiate
antagonists is of clinical relevance. Although N-allyl-norcodeine was first described in
1915, the discovery of the antagonist effects produced by substituting three-carbon side
chains on the morphine molecule came only in the early 1940s. Nalorphine (5.97) was
the first clinically useful antagonist, having a dramatic reviving effect on patients on the
verge of death from opiate-induced respiratory failure. It also precipitates withdrawal
symptoms in addicts. However, although nalorphine is a mixed opiate agonist–antagonist
and thus a potentially valuable nonaddicting drug, its unpleasant psychomimetic and
hallucinogenic properties preclude its use as an analgesic.
The analogous compound derived from 14-hydroxymorphone, naloxone (5.98), was
discovered in 1961 and is a pure antagonist. Its cyclopropylmethyl analog, naltrexone
358 MEDICINAL CHEMISTRY