Indole.This is a bicyclic (one five-membered ring plus one six-membered ring) aromatic
heterocycle. Since most indole-containing drugs are substituted with the remainder of
the drug being positioned at the 3 position, the aromatic hydroxylation tends to occur
at the 4–7 position.
Coumarin.The coumarin moiety is found in a number of important drugs. This is a
bicyclic heterocycle containing two six-membered rings and two oxygens, one endo-
cyclic, one exocyclic. Since the coumarin contains an intramolecular lactone ester, it
undergoes hydrolysis to yield a carboxylic acid and a phenol.
3.5.2 Site of Delivery ConsiderationsThe next major consideration during optimization for the pharmacokinetic/pharmaceutical
phase concerns the design of drugs to overcome barriers during their distribution. Of
these barriers, the blood–brain barrier is by far the most important to the drug designer.
3.5.2.1 The Blood–Brain Barrier
The blood–brain barrier (BBB) is both a friend and a foe to the drug designer. When
designing a drug for a non-neurologic condition, the BBB is a friend in that it can be
used to preclude entry of the drug into the brain, thereby decreasing side effects.
However, when designing a drug for a neurological indication, the BBB is a true bar-
rier that must be crossed. Moreover, if a drug has been designed to cross the BBB, it
typically will also cross the maternal–fetal placental barrier — a consideration when
designing drugs that may be used in women of childbearing age.
The notion of a BBB first emerged in the early years of the twentieth century when it
was observed that organic dyes injected into animals stained all tissues except the brain.
There appeared to be some invisible barrier that prevented certain molecules from enter-
ing into the brain. Over the past twenty to thirty years, the structural basis of the BBB
has been more carefully delineated. Many different structural components contribute to
the BBB.
The small blood vessels, or capillaries, are the first structural level of the BBB. Drug
molecules are distributed throughout the body by the bloodstream and the capillary is the
point at which a drug leaves the bloodstream to bind to a receptor. Within the brain, cap-
illaries are composed of cells, called endothelial cells, that are connected to each other by
tight junctions. These junctions are a first-line impediment, slowing the journey of the
drug molecule from within the capillary to a receptor site on a neuron. The next compo-
nent of the BBB is the astrocyte. The astrocyte is a glial cell(helper cell) within the brain.
The astrocyte wraps itself around the capillary to provide yet another line of defense
between the drug in the capillary and the neuronal receptor to which it is traveling. The
tight junction–astrocyte barrier is unique to the brain and forms the BBB (see figure 3.9).
There are two methods for crossing the BBB: passive diffusion or active transport.
Passive diffusion is the route preferred by most neuroactive drugs. Lipid solubility is a
desired chemical property for a molecule to diffuse across the BBB. For a molecule to
cross the BBB by passive diffusion it should have a molecular weight less than 650 g/mol
and should have a logP(logarithm of the octanol–water partition coefficient) value
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 153