is not conformationally constrained. Many publications have proposed receptor mapping
techniques based on the distances between assumed key atoms (usually heteroatoms) or
functional groups in drugs, determined by prolonged quantum-chemical calculations of
“preferred” conformers. Similarly, the design of a number of drugs has been based on
questionable assumptions about drug–receptor binding, all founded on conformational
analysis. These oversimplifications are subject to criticism. Such caveats, however, do
not detract from the utility of conformational analysis of drugs, from the importance of
calculating intergroup geometric distances, or from the potential value of these methods
in drug design and molecular pharmacology.
Flexible molecules that lack conformational constraints may assume a variety of dif-
ferent conformations, thus increasing the likelihood of drug toxicity by enabling inter-
actions with undesirable receptor sites. The drug designer may address these problems
by using various methods to decrease the degrees of conformational freedom. For
instance, within the hydrocarbon skeleton of a drug, an alkane moiety could be replaced
by either an alkene or an alkyne; the increased barrier to rotation around double or triple
bonds (as compared to single bonds) adds a considerable measure of conformational
constraint. However, one of the most popular techniques for decreasing conformational
freedom is to replace acyclic hydrocarbon fragments with cyclic fragments, such as
cyclohexane rings or aromatic rings.
The conformational analysis of cyclohexane and its derivatives has been well explored.
The cyclohexane ring itself can assume several conformations. The chair conformation is
more stable than either the boat or twist form because it permits the maximum number of
substituents to exist in a staggered conformation relative to their neighbors. The sub-
stituents can assume two conformations relative to the plane of the ring (defined by
carbon atoms 2, 3, 5, and 6):axial(a), in which they point up or down; and equatorial(e),
in which they point in the direction of the ring’s circumference. As the cyclohexane ring
keeps flipping back and forth between many chair forms, the substituents on the ring alter-
nate between axial and equatorial conformations unless stabilized (see figure 1.10).
Although cyclohexane is more conformationally rigid than an acyclic hydrocarbon, there
are several ways to additionally stabilize or “freeze” the conformation of a cyclohexyl ring.
- By electrostatic repulsion of two adjoining substituents (e.g., in 1,2-dichlorocyclohexane,
a diaxial conformation is forced). - By steric repulsion.
- By using a bulky substituent like the tert-butyl group, which always maintains an
equatorial position. - By using multiple cyclohexyl rings adjoined to each other.
The use of multiple adjoined rings is an effective means of locking conformation.
Polycyclic structures, such as decaline or the steroids, are rigid and maintain stable
conformations. In such rigid systems, the axial and equatorial substituents can display
34 MEDICINAL CHEMISTRY