some of the bewildering variations of rings in the older H 1 antihistamines reveals them
to be simply variations on the ethylenediamine structure, differing only quantitatively
in their effect. Sometimes, however, relatively minor changes in ring structure lead to
profound qualitative changes. The most famous example of this occurs in the transition
from the neuroleptic dopamine-blocking phenothiazine drugs to the antidepressant
dibenzazepines such as imipramine, in which the replacement of -S- by -CH 2 -CH 2 -
changes the molecular geometry.
Ring opening or closure usually leads to subtle changes in activity, provided that
nothing else changes. Three examples (among many possibilities) come to mind: incor-
poration of the N-methyl substituents of chlorpromazine (1.3) into a closed piperazine
ring in prochlorperazine tremendously increases the antiemetic effect while the neu-
roleptic activity declines. Of course, this may be due to the introduction of a new basic
center. In thioridazine (3.9), the neuroleptic effect increases with the introduction of a
closed ring, but extrapyramidal side effects (tremor, stooped posture, slow and shuffling
gait) become noticeable.
The inclusion of rings helps to conformationally constrain a molecule and make it less
flexible. As discussed in the previous section, this is a desirable design strategy.
Incorporating alkyl rings may change the solubility of the molecule, increasing lipophilic-
ity. The incorporation of an aromatic ring may change the pharmacokinetics of the drug.
3.4.1.4 Structure Pruning and Addition of Bulk
As noted earlier, the pharmacophore of a drug is usually confined to a few functional
groups or parts of the whole molecule, which can be a large one. In the case of such com-
plex natural products as alkaloids, which may be difficult or impractical to synthesize
(e.g., tubocurarine (3.10)), the first design attempt is usually directed at simplification
of the molecule, pruning away those structural elements that are not part of the phar-
macophore and do not serve to hold crucial binding groups in their appropriate posi-
tions. The most successful dissection of a molecule can be seen in the case of morphine.
Starting with morphine (3.11), the oxygen bridge (i.e., the furan ring) is first removed,
resulting in levorphanol (3.12), a morphinan. By eliminating ring C, the benzomorphan
series is obtained. Its most successful member is pentazocine (3.13), which retains only the
two methyl groups from ring C and has a lower addiction liability. The simplest (and,
incidentally, oldest) modification of the morphine molecule is seen in meperidine (3.14),
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 137