TheN-methyl substituenton morphine is not absolutely essential to its analgesic
activity; such activity is instead more a question of the proper partition coefficient. Thus
N-normorphine, the secondary amine, has only one-eighth of the central activity of
morphine but is equiactive with the latter on the guinea pig ileum, indicating that it can-
not cross the blood–brain barrier because of its polarity. Higher alkyl substituents usu-
ally render the molecule less active, although the activity rises dramatically if the side
chain carries an aromatic ring. For instance, the N-furfurylmethyl- and N-phenethyl-
normorphine derivatives and their analogs can be up to 50 times more active than
morphine as a result of the involvement of auxiliary binding sites.
The most important and dramatic change results when the N-methyl group of mor-
phine is replaced by an N-alkene or N-cyclopropylmethyl group. The resulting com-
pounds show antagonist properties.
Derivatives with a C-14 hydroxyl groupsuch as oxymorphone (5.89, 7, 8-dihydro-
14-hydroxymorphine-6-one) show increased potency (up to five times that of mor-
phine), probably as a result of the introduction of an additional hydrogen-bonding
substituent. The stereochemistry of this hydroxyl is of considerable importance in terms
of activity.
5.18.9 Synthetic Morphine AnalogsMolecular modifications in the form of simplifications of the morphine ring system
have been undertaken for many years, and have resulted in the development of some
spectacularly successful compounds devoid of addictive properties.
5.18.9.1 Morphinans
Omission of the furan ring (i.e., oxygen bridge) of morphine results in compounds
known as morphinans, such as (−)levorphanol (3.12), which is five to six times more
active than morphine. Loss of the phenolic hydroxyl decreases the activity of this com-
pound to 20% of that of morphine. The (+) isomer, dextrorphan (5.90), is totally devoid
of analgesic activity because it cannot bind to the receptor. However, dextrorphan has
antitussive properties that are valuable, and is used in the form of its methyl ether (dex-
tromethorphan). Shifting of the phenolic hydroxyl group to position 2 or 4 results in a
total loss of activity. The N-phenethyl (5.91) derivative of levorphanol shows an anal-
gesic effect about twenty times greater than that of the parent compound.
356 MEDICINAL CHEMISTRY