women to make their ocular pupils look darker and thus supposedly more attractive),
and cocaine (8.88, from Erythroxylon coca). In medicinal chemistry, cocaine was the
starting point in the design of many local anesthetic agents, including lidocaine and pro-
caine. Alkaloids such as atropine and cocaine contain a pyrrolidine ring that is bridged
by three carbon atoms between the second and fifth carbons; hence, they are sometimes
referred to as tropane alkaloids. Alkaloids containing an isoquinoline or reduced iso-
quinoline ring are likewise medically important. Papaverine (8.89), morphine (8.90),
and codeine (8.91) are all alkaloids obtained from the opium poppy,Papaver som-
niferum. Papaverine has an isoquinoline ring; morphine and codeine contain a partially
reduced isoquinoline ring. These compounds have played a central role in the design of
analgesic agents for the treatment of pain. Alkaloids containing indole rings have also
been used medically. Reserpine (8.92), obtained from the Indian snakeroot plant
(Rauwolfia serpentina), was used in aboriginal medicine for centuries as a “tranquil-
izer” and in modern medicine as an agent to treat systemic arterial hypertension (high
blood pressure).
Semisynthetic heterocycles are also important drug molecules. These compounds
attempt to capture the best of both worlds, being synthetic derivatives of natural prod-
ucts. The use of a natural product in the preliminary stages of the synthesis enables the
elimination of numerous costly synthetic steps. The subsequent synthetic modifications
enable further fine tuning of the natural product pharmacophore. There are a number of
semisynthetic penicillin derivatives available. Similarly, there are also semisynthetic
hormone analogs, especially of estrogens and gestagens.
Finally, there are numerous purely synthetic heterocycles. These are discussed in
many places throughout this book. The hydantoin ring of phenytoin and the barbiturate
ring of phenobarbital are good examples of these. There are a variety of drugs contain-
ing pyrrolidine, furan, pyrazole, pyridine, and indole rings.
8.7.1 Porphyria and Diseases Influencing
Heterocycle-Based Drug DesignPorphyrins are endogenous heterocycles formed by the linkage of four pyrrole rings
through methylene bridges. As discussed previously, porphyrins play an important role
in crucial biomolecules, such as hemoglobin or myoglobin. Porphyria is a disorder of
porphyrin metabolism that may be either inherited or acquired; thus, porphyria
embraces a group of diseases, each with unusual and characteristic manifestations,
which have in common the excessive excretion of one or more of the porphyrins and/or
porphyrin biosynthetic precursors.
Of the various types of porphyria, one type (acute intermittent porphyria, AIP) is
relevant to medicinal chemistry and drug design. Clinically, AIP is characterized by
periodic attacks of intense abdominal pain, severe nausea and vomiting, psychotic
behavior, disturbances of neuromuscular transmission (which may even lead to quadri-
plegia), and occasionally death. In AIP, the basic defect lies in an enzyme called por-
phobilinogen deaminase. Acute and potentially life-threatening attacks of AIP can be
brought on by certain drugs. The drugs that precipitate porphyria are inducers of hepatic
cytochrome P-450, an important heme-containing enzyme found in the liver. Drugs that
have been implicated in porphyria exacerbations are structurally diverse and include
ENDOGENOUS MACROMOLECULES 531