5.18.9.2 Benzomorphan and Metazocine Series
Opening of the C ring as well as omission of the D ring of morphine results in the 6,7-
benzomorphan series. Two methyl groups were retained on ring B. Study of the stere-
ochemistry of these methyl groups has led to the major discovery of nonaddictive
analgesics of the metazocine series. Compounds in which the two alkyl substituents
arecis(as are the corresponding carbon atoms in morphine) are powerful analgesics.
However, they cannot relieve withdrawal symptoms in addicted animals, which means
that these drugs are not addictive. The transisomers, on the other hand, while also
potent analgesics, will relieve withdrawal. The (−) isomers in this series will precipitate
withdrawal symptoms in addicted animals even with an N-methyl (that is, agonist) sub-
stituent, which indicates that they are mixed agonist–antagonists. Although there are
complicating factors and exceptions to this rule with some of the compounds, deriva-
tives of exceptionally low addictive capacity and satisfactory analgesic potency have
been prepared, such as pentazocine (3.13), which can be used in chronic applications
without the danger of addiction. Some of these derivatives, like the N-cyclopropylmethyl
compound (5.92, cyclazocine), cannot be used because of unpleasant dysphoric and
hallucinogenic properties. Another benzomorphan, bremazocine (5.93), is a powerful κ
agonist of long duration, and is devoid of addictive properties and respiratory depres-
sant activity. On the basis of receptor binding, it is about 200 times more active than
morphine and has a very low sodium shift, like all of the mixed agonist– antagonist (or
metagonist) benzomorphans.
5.18.9.3 Piperidine Derivatives
Piperidine derivatives represent the ultimate simplification of the morphine skeleton.
They were first developed in the 1940s, and one—meperidine (3.14, Demerol)—is per-
haps still the most widely used synthetic opiate in clinical practice despite its addictive
properties. It is obviously a morphine analog, but only the A and E rings are retained.
The addition of a 3-OH group results in the bemidone (5.94) series, while modifica-
tion of the ester group to a ketone gives the ketobemidones (5.95), which have more
than six times the activity of meperidine. The derivative carrying the N-phenethyl
side chain (5.96, anileridine) has also proved to be potent. Remarkably, N-alkene or
N-cyclopropylmethyl derivatives in this series do not show antagonist properties. It
should be noted that the original C-13 must be quaternary in all of these compounds.
HORMONES AND THEIR RECEPTORS 357